Compounds for producing sulfonamide or sulfinamide compounds that have BRD4 proteolytic activity.

Abstract

To provide a compound which is superior in an action inducing degradation of BRD4 protein and useful as a therapeutic agent for cancer, or a pharmaceutically acceptable salt thereof.SOLUTION: Provided is a compound represented by the formula (I) in the figure or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to sulfonamide or sulfinamide compounds or pharmaceutically acceptable salts thereof that are excellent in cytotoxic activity against cancer cells, activity in inducing the degradation of BRD4 protein in cancer cells, and activity in inhibiting the binding of BRD4 protein to acetylated histones, and are useful as anticancer agents, BRD4 protein degradation inducers, and BRD4 protein inhibitors, as well as compounds for producing them. [Background technology]

[0002] Eukaryotic DNA is stored in the nucleus, forming a chromatin structure. The nucleosome, its constituent unit, has a structure in which DNA is wrapped around a histone octamer, which is composed of two molecules each of four types of histones: H2A, H2B, H3, and H4. The tens of residues at the N-terminus of a histone are called the histone tail, and various post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination exist there. These post-translational modifications, also known as the histone code, are one of the mechanisms responsible for epigenetic gene expression control, determining "when" and "where" genetic information on DNA is expressed. Histone modification is reversible and is functionally controlled by modifying enzymes (writers) that write modifying groups to histones, demodifying enzymes (erasers) that remove modifying groups, and histone readers that specifically read modified histones. These regulatory mechanisms greatly contribute to individual development and cell differentiation, and it is known that abnormalities in epigenetics are involved in various diseases.

[0003] Bromodomains are reader proteins consisting of approximately 110 amino acids that recognize acetylated lysine on histones. Approximately 50 types of proteins possessing bromodomains are known to date. By binding to acetylated lysine on histones, they function as scaffold proteins for various transcription factors, and also exert various functions within cells, such as chromatin reconstitution and transcriptional regulation through their own histone acetyltransferase and kinase activity. BRD2, BRD3, BRD4, and BRDT, which are included in the BET (bromodomain and extraterminal) family of bromodomain-possessing proteins (sometimes referred to as BET proteins in this specification and in the claims), possess two highly conserved bromodomains at the N-terminus and an extra C-terminal domain at the C-terminus, and each BET protein is known to function both independently and cooperatively (Non-Patent Literature 1).

[0004] Among the BET family proteins, BRD4 regulates the expression of the proto-oncogene c-MYC (Non-Patent Literature 2), and has been reported to correlate with prognosis in various cancers, such as gastric cancer (Non-Patent Literature 3), ovarian cancer (Non-Patent Literature 4), lung cancer (Non-Patent Literature 5), liver cancer (Non-Patent Literature 6), urothelial carcinoma (Non-Patent Literature 7), testicular cancer (Non-Patent Literature 8), skin cancer (Non-Patent Literature 9), prostate cancer (Non-Patent Literature 10), breast cancer (Non-Patent Literature 11), colorectal cancer (Non-Patent Literature 12), and leukemia (Non-Patent Literature 13). For these reasons, it is expected to be a target for drug discovery in cancer treatment.

[0005] To date, BRD4 inhibitors, which inhibit the binding of BRD4 to histones, have been clinically developed as anticancer drugs targeting BRD4 (Non-Patent Literature 14). However, BRD4 inhibitors do not show sufficient effect to cause BRD4 accumulation (Non-Patent Literature 15), and resistance is acquired through the expression of proteins that stabilize BRD4 expression or proteins that enhance BRD4-mediated transcriptional activity independently of the bromodomain (Non-Patent Literature 16, 17). Therefore, there is a need for the development of anticancer drugs targeting BRD4 by new means.

[0006] In recent years, ligands for E3 ligases with ubiquitin ligase activity [Von Hippel-Lindau (VHL), Cereblon (CRBN), Cellular Inhibitor of Apoptosis Protein 1 (cIAP1)] have been identified. Chemical knockdown, a technique that uses a compound linked to a binder that binds to the target protein to form an artificial complex of E3 ligase and the target protein within the cell, and induces the degradation of the target protein by utilizing the ubiquitin-proteasome system, an intracellular protein degradation mechanism, is attracting attention as a new drug discovery technology (Non-Patent Literature 18). To date, BRD4 protein degradation inducers utilizing this technology have been reported, such as ARV-771, which uses a ligand for VHL, and ARV-825, which uses a ligand for CRBN (Non-Patent Literature 15, 19).

[0007] In cancer chemotherapy, the emergence of spontaneous resistance, where anticancer drugs are ineffective from the start of treatment, and acquired resistance, where the effectiveness of anticancer drugs decreases with long-term use, are major problems (Non-Patent Literature 20). Overcoming this resistance to anticancer drugs is expected to lead to improved treatment outcomes in cancer chemotherapy, and various resistance mechanisms have been revealed to date (Non-Patent Literature 20). Regarding BRD4 proteolytic agents, it has been reported that acquired resistance is induced in cancer cells by dysfunction of the complex of the E3 ligase VHL or CRBN, which provides proteolytic activity (Non-Patent Literature 21). Furthermore, in tumors such as renal cell carcinoma caused by mutations in the VHL gene (Non-Patent Literature 22), spontaneous resistance to BRD4 proteolytic agents using ligands for VHL is thought to be observed, and the development of novel BRD4 proteolytic agents using ligands for new E3 ligases that overcome the resistance of conventional BRD4 proteolytic agents is desired. In recent years, many targeted proteolytic compounds have been reported in which ligands for new E3 ligases are bound to binders for target proteins (Non-Patent Literature 23). For example, a BRD4 proteolytic agent utilizing the new E3 ligase DCAF15 has been reported (Non-Patent Literature 24). However, its BRD4 proteolytic and cytotoxic effects are not considered sufficient. Currently, the combinations of ligands for E3 ligases and binders for target proteins are limited (Non-Patent Literature 23), and it is necessary to find an appropriate combination of ligand and linker structure for E3 ligases that will exhibit sufficient BRD4 proteolytic and cytotoxic effects as an anticancer agent for binders for BRD4 proteins. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Taniguchi Y., Int J Mol Sci. 2016, 17: E1849 [Non-Patent Document 2] Kanno T., Nat Struct Mol Biol. 2014, 21: 1047-1057 [Non-licensed document 3] Zhu Y., Oncotarget. 2017, 8: 31092-31100

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Non-licensed literature 9

Non-licensed literature 10

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Non-licensed Document 14

[0009] The present invention aims to provide a compound or a pharmaceutically acceptable salt thereof that exhibits excellent BRD4 proteolytic activity using a ligand for the E3 ligase DCAF15 and is useful as a cancer treatment agent. [Means for solving the problem]

[0010] The present inventors, through diligent research to solve the above problems, have discovered a compound that has BRD4 proteolytic activity using a ligand for the E3 ligase DCAF15, and have found that it can provide a therapeutic agent for cancer. In particular, by finding an optimal linker structure for the ligand for DCAF15, the present invention has been completed. In other words, the gist of the present invention is as follows.

[0011] [1] Equation (I):

[0012] [ka]

[0013] [In the formula, A and Q independently represent rings selected from: aromatic hydrocarbon rings; aromatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen; cycloalkane rings; and aliphatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen. The ring is, halogen atom; Hydroxyl group; Cyano group; Hydroxycarbonyl group; Oxo group; Thioxo group; Alkyl groups that may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups; An alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; An alkoxycarbonyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; -CO-N(R 7a )(R 7b ); -N(R 7a )(R 7b );and -N(R 7c )-CO-R 7d ; which may be substituted with a group selected from Z 1 is a group selected from C and N, Z 2 is a group selected from C and N, Z 3 is a group selected from =CR Z3 - and =N-, Z 4 is a group selected from =CR Z4 - and =N-, Z 5 is a group selected from =CR Z5 - and =N-, R Z3 R Z4 and R Z5 are independent of each other, hydrogen atom; halogen atom; hydroxy group; cyano group; hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; a cycloalkyl group which may be substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; an alkoxy group which may be substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; an alkoxycarbonyl group which may be substituted with a group selected from halogen atom, hydroxy group, alkoxy group and cyano group; -CO-N(R 7a )(R 7b ); -N(R 7a )(R 7b ); -N(R 7c )-CO-R 7d ; aromatic hydrocarbon group; and a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen; represents a group selected from, Substructural formula:

[0014]

Chemical formula

[0015] This is expressed by the following formulas (Ea), (Eb), or (Ec):

[0016] [ka]

[0017] Show one of the following: L, T, and M each independently exhibit a single bond, -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -;-SO2-NR 7c -R 7r -; and -R 7r -SO2-NR 7c -; indicates a base selected from, This refers to a group selected from: a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group that may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkylene group. The group may be substituted with substituents selected from halogen atoms; hydroxyl groups; cyano groups; oxo groups; hydroxycarbonyl groups; alkyl groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups. -LTM- is a structure that is all or part of -OO-, -SS-, -NR 7a -NR 7a -, -OS-, -SO-, -O-NR 7a -, -NR 7a -O-, -S-NR 7a - and -NR 7a It does not indicate the group selected from -S-, G indicates N or C. J indicates N or O. Further substructure:

[0018] [ka]

[0019] teeth,

[0020] [ka]

[0021] Show the substructure selected from, n is either 1 or 2. m represents an integer from 1 to 6. R 5 is a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; R 7a and R 7b These are alkyl groups that may be independently substituted with a hydrogen atom or a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group. R bonded to the same nitrogen atom 7a and R 7b It may bond to form an aliphatic heterocycle containing one nitrogen atom, which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, along with the nitrogen atom. R 7c and R 7d These are alkyl groups that may be independently substituted with a hydrogen atom or a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. R 7r is a group selected from: an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; R 8a and R 8b These are groups that are independently selected from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; R 9a and R 9b These are, independently of each other, a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; an alkoxy group which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; an alkoxycarbonyl group which may be substituted with a substituent selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and -CO-N(R 7a )(R 7b ); is it a base selected from, R 9a and R 9bTogether, they may form a fused ring with the adjacent ring E, exhibiting an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; or an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. R 10a and R 10b These are, independently of each other: hydrogen atom; hydroxyl group; cyano group; -N(R 7a )(R 7b );-N(R 7c )-CO-OR 7d The substituents selected from ; and alkyl groups; are shown. The alkyl group is, Halogen atom; hydroxyl group; cyano group; alkoxy group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; hydroxycarbonyl group; and -CO-N(R 7a )(R 7b ); may be substituted with substituents selected from, or, R 10a and R 10b Together, they form a ring showing an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. R 11 [The group is selected from a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group.] A compound represented by or a pharmaceutically acceptable salt thereof (which may be abbreviated as "compound (I)" in this specification).

[0022] [2] Substructure:

[0023] [ka]

[0024] is represented by the following formula:

[0025] [Chemical formula]

[0026] [In the formula, R a represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; R a’ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ); R a’’ represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; or -CO-N(R 7a )(R 7b ).] represented by the compound according to [1] or a pharmaceutically acceptable salt thereof.

[0027] [3] A is a ring selected from an aromatic hydrocarbon ring, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 atoms selected from oxygen, sulfur and nitrogen, and a cycloalkane ring, R Z3 is This indicates a group selected from: hydrogen atom; halogen atom; hydroxyl group; cyano group; hydroxycarbonyl group; alkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; cycloalkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxy group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; R Z4 and R Z5 These independently represent a group selected from: a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; Substructure:

[0028] [ka]

[0029] However, the following formula (Ea) or (Ec):

[0030] [ka]

[0031] Show, Substructure:

[0032] [ka]

[0033] but,

[0034] [ka]

[0035] shows Substructure:

[0036] [Chemical formula]

[0037] where

[0038] [Chemical formula]

[0039] shows L is a group selected from a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkynylene group, the group may be substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group, T represents a single bond, -CO-, -CO-NR 7c -, -NR 7c -CO-, or -O-, or it is an alkylene group which may be substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; and an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group, M is a single bond, or -O-; -S-; -NR 7a -; -CO-; -SO-; -SO2-; -CO-NR 7c -; -NR 7c-CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; and alkylene groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; alkynylene groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and divalent aliphatic heterocyclic groups which may be substituted with substituents selected from a) halogen atoms, b) hydroxyl groups, c) cyano groups, d) oxo groups, e) alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups, and f) alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; R 5 That is a hydrogen atom, R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7c That is a hydrogen atom, R 8a and R 8b These are groups that are independently selected from hydrogen atoms; halogen atoms; hydroxyl groups; and cyano groups. R 9a and R 9bHowever, each group is independently selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; R 10a and R 10b These are independent of each other, hydrogen atoms;-N(R 7c )-CO-OR 7d The substituents selected from ; and alkyl groups; are shown. The alkyl group in question is Halogen atom; hydroxyl group; cyano group; alkoxy group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; -CO-N(R 7a )(R 7b ); and hydroxycarbonyl groups; may be substituted with substituents selected from these, [2] The compounds described therein or pharmaceutically acceptable salts thereof.

[0040] [4] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring, R a However, it represents an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R a’ However, it represents an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R a’’ However, it represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group. R Z3However, it represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; R Z4 and R Z5 These independently represent a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; Substructure:

[0041] [ka]

[0042] However, the following equation (Ea):

[0043] [ka]

[0044] Show, L is a group selected from: an alkynyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a) halogen atom, b) hydroxyl group, c) cyano group, d) alkyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups, and e) alkoxy group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; and a divalent aromatic heterocyclic group containing one to two atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may be partially hydrogenated. The aromatic heterocyclic group may be substituted with substituents selected from halogen atoms, hydroxyl groups, cyano groups, and oxo groups. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; Is M a single bond? -R 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; an alkynylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; and a divalent aliphatic heterocyclic group; a group selected from these, R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7r This represents an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, these alkyl groups may be substituted with substituents selected independently from halogen atoms, hydroxyl groups, and cyano groups. R 10a hydrogen atoms; as well as halogen atoms, hydroxyl groups, cyano groups, -NH-CO-OR 7d ,-CO-N(R 7a )(R 7b), an alkyl group which may be substituted with substituents selected from alkoxycarbonyl groups and hydroxycarbonyl groups; R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. The compounds described in [2] or [3] or their pharmaceutically acceptable salts.

[0045] [5]R a However, it represents a hydrogen atom; or an alkyl group. R a’ However, it represents a hydrogen atom; or an alkyl group. R a’’ However, it represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group. R Z3 However, it represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom and a hydroxyl group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 Each independently represents a hydrogen atom; or an alkyl group; Substructure:

[0046] [ka]

[0047] However, the following equation (Ea):

[0048] [ka]

[0049] Show, L is a group selected from: an alkylylene group; a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 substituents selected from halogen atoms, hydroxyl groups, alkyl groups which may be substituted with 1 to 3 halogen atoms, and alkoxy groups; a divalent aliphatic heterocyclic group which contains one nitrogen atom; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. When the aromatic heterocyclic group is a partially hydrogenated, divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, it may be substituted with an oxo group. Is T a single bond? -CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; Is M a single bond? -R 7r -O-;-R 7r -NR 7a -; an alkylene group that may be substituted with one hydroxyl group; an alkylylene group; and a divalent aliphatic heterocyclic group; are selected from these groups. R 6a and R 6b These are groups that are independently selected from hydrogen atoms; halogen atoms; cyano groups; and alkyl groups. R 7a and R 7b However, each independently represents a hydrogen atom; or an alkyl group, R 7c This represents a hydrogen atom. R 7d This indicates an alkyl group. R 7r This shows an alkylene group, R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, they may also be substituted with a single hydroxyl group independently of each other. It is a kill group, R 10a is a hydrogen atom; and -NH-CO-OR7d ,-CO-N(R 7a )(R 7b ), one selected from a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group A group selected from alkyl groups which may be substituted with substituents; R 10b That is a hydrogen atom, R 11 is an alkyl group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items [2] to [4].

[0050] [6] A represents a benzene ring, R a However, it shows a hydrogen atom. R 10a However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with one or two substituents selected from a halogen atom, an alkyl group which may be substituted with one to three halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains one or two atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. M is an alkylene group which may be substituted with one substituent selected from a hydroxyl group and a cyano group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items [2] to [5].

[0051] [7]R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it represents an alkyl group or alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups, R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. A compound or a pharmaceutically acceptable salt thereof as described in any one of items [2] to [6].

[0052] [8]R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, these alkyl groups may be independently substituted with one hydroxyl group each. R 10a However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. , R 10b That is a hydrogen atom, R 11 is an alkyl group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items [2] to [7].

[0053] [9]L is a phenylene group or a pyrazinediyl group, which may be substituted with one or two substituents selected from halogen atoms and alkyl groups. T is -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2- or -CH(CH3)-. A compound or a pharmaceutically acceptable salt thereof as described in any one of items [2] to [8].

[0054]

[10] Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(3'-chloro-4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, 5-Chloro-N-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxamide, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridine-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',5'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2'-fluoro-5'-methyl[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-2',3'-difluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazine-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazine-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridine-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, and t-butyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate A compound selected from, or a pharmaceutically acceptable salt thereof.

[0055]

[11] Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, t-butyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, t-butyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}-3'-fluoro[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, 5-Chloro-N-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-2-fluoro-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxamide, Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2',3'-difluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridine-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazine-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(5-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyrazine-2-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, Methyl [(6S)-4-(4-{5-[(2-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyrazine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate, Methyl {(6S)-4-[4-(6-{[(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}pyridine-3-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate, and Methyl [(6S)-4-(4-{6-[(2-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate A compound selected from, or a pharmaceutically acceptable salt thereof.

[0056] A pharmaceutical composition comprising any one of the compounds described in

[12] [1] to

[11] or a pharmaceutically acceptable salt thereof.

[13] The pharmaceutical composition described in

[12] for inducing BRD4 proteolysis.

[14] The pharmaceutical composition according to

[12] or

[13] for the treatment of cancer.

[15] The pharmaceutical composition according to

[14] , wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia / lymphoma, Burkitt lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, cholangiocarcinoma, renal cell carcinoma, and fibrosarcoma.

[16] The pharmaceutical composition according to

[15] , wherein the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma.

[17] The pharmaceutical composition according to

[16] , wherein the cancer is selected from acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

[18] Use of any one of the pharmaceutical compositions described in

[12] to

[17] for the treatment of cancer.

[19] Use of any one of the compounds described in [1] to

[11] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer. A method for treating cancer, comprising administering a compound described in any one of items

[20] (1) to

[11] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of items

[12] to

[17] . [Effects of the Invention]

[0057] The compounds of the present invention exhibit excellent BRD4 protein degradation-inducing activity and are useful as cancer treatment agents. [Brief explanation of the drawing]

[0058] [Figure 1] The results of the BRD4 protein degradation induction effect in Test Example 4 are shown. [Figure 2] The results of the antitumor effect in test example 6 are shown. [Modes for carrying out the invention]

[0059] The compounds of the present invention are compounds represented by general formula (I) or pharmaceutically acceptable salts thereof. In this specification, "compounds represented by general formula (I) or pharmaceutically acceptable salts thereof" may be collectively referred to as the compounds of the present invention. The following definitions of terms used in this specification are provided, and the present invention will be described in more detail below. However, the following definitions of terms are not intended to limit the present invention in any way.

[0060] In this specification, "halogen atoms" include, for example, fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0061] In this specification, "alkyl group" refers to, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. 1-6 "Alkyl group" is one example.

[0062] In this specification, "cycloalkyl group" refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl, etc. 3-10 Examples include "cycloalkyl groups."

[0063] In this specification, "alkoxy group" refers to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. 1-6 An example is the "alkoxy group."

[0064] In this specification, "alkylene group" refers to, for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -CH(C3H7)-, -CH(CH(CH3)2)-, -(CH(CH3))2-, -CH2-CH(CH3)-, -CH(CH3)-CH2-, -CH2-CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-CH2-, etc. 1-6 An example is the "alkylene group."

[0065] In this specification, "alkenylene group" refers to, for example, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -C(CH3)2-CH=CH-, -CH=CH-C(CH3)2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH2-CH2-, -CH=CH-CH2-CH2-CH2-, -CH2-CH2-CH2-CH=CH- etc. 2-6 An example is the "alkenylene group".

[0066] In this specification, "alkynylene group" refers to, for example, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C(CH3)2-C≡C-, -C≡CC(CH3)2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡C-CH2-CH2-, -C≡CC≡C-, -C≡C-CH2-CH2-CH2-, -CH2-CH2-CH2-C≡C-, etc. 2-6 An example is the "alkynylene group."

[0067] In this specification, "cycloalkylene group" refers to, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, etc. 3-10 One example is the "cycloalkylene group."

[0068] In this specification, "alkoxycarbonyl group" refers to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. 1-6 An example is the "alkoxy-carbonyl group".

[0069] In this specification, "cycloalkane ring" refers to, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. 3-10 One example is the "cycloalkane ring."

[0070] In this specification, "aromatic hydrocarbon ring" refers to, for example, "C" such as benzene, naphthalene, and anthracene. 6-14 An example is the "aromatic hydrocarbon ring."

[0071] In this specification, "aromatic hydrocarbon group" refers to, for example, C1, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, etc. 6-14 An example is the aryl group.

[0072] In this specification, "divalent aromatic hydrocarbon group" refers to, for example, C such as phenylene, naphthylene, and anthrylene. 6-14 An example is the arylene group.

[0073] In this specification, "aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" refers, for example, to a 3 to 14-membered (preferably 4 to 10-membered) aliphatic heterocycle containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen in addition to carbon atoms as ring constituent atoms. Suitable examples of the "aliphatic heterocycle" include aziridine, oxirane, thiran, azetidine, oxetane, thietan, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazolline, pyrazolidine, thiazoline, thiazolidin, tetrahydroisothiazole, tetrahydroxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanin, diazepan, azepine, azocan, diazocan, oxepan, and other 3- to 8-membered monocyclic aliphatic heterocycles; Examples include 9 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aliphatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthidine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline.

[0074] In this specification, "aliphatic heterocycle containing one nitrogen atom" refers, for example, to an aliphatic heterocycle containing one nitrogen atom among the "aliphatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" mentioned above.

[0075] In this specification, "divalent aliphatic heterocyclic group" refers, for example, to a divalent aliphatic heterocyclic group derived from the above-mentioned "aliphatic heterocyclic ring".

[0076] In this specification, "a divalent aliphatic heterocyclic group containing one nitrogen atom" refers, for example, to a divalent aliphatic heterocyclic group derived from an aliphatic heterocyclic ring containing one nitrogen atom among the above-mentioned "aliphatic heterocyclic rings".

[0077] In this specification, "aromatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen" include, for example, 5 to 14-membered (preferably 5 to 10-membered) aromatic heterocycles containing 1 to 3 atoms selected from oxygen, sulfur, and nitrogen in addition to carbon atoms as ring constituent atoms. Preferred examples of such "aromatic heterocycles" include 5 to 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, phlopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, phlopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine Examples include 8 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocycles such as pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxatiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carbolin, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0078] In this specification, "a 5-6 member aromatic heterocyclic group containing 1-3 atoms selected from oxygen, sulfur, and nitrogen" refers, for example, to a 5-6 member aromatic heterocyclic group containing 1-3 atoms selected from oxygen, sulfur, and nitrogen in addition to carbon atoms as ring constituent atoms. Suitable examples of the "aromatic heterocyclic group" include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl, which are 5- to 6-membered monocyclic aromatic heterocyclic groups.

[0079] In this specification, "divalent aromatic heterocyclic groups that may be partially hydrogenated" include, for example, the "aliphatic heterocyclic rings" and divalent ring groups derived from the "aromatic heterocyclic rings."

[0080] In this specification, "a divalent aromatic heterocyclic group containing one to two atoms selected from nitrogen, oxygen, and sulfur atoms, which may be partially hydrogenated" refers, for example, to a divalent ring group derived from the above-mentioned "aliphatic heterocyclic ring" and a ring containing one to two atoms selected from nitrogen, oxygen, and sulfur atoms among the above-mentioned "aromatic heterocyclic ring." Among the "divalent aromatic heterocyclic groups containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, which may be partially hydrogenated," a preferred example of the "partially hydrogenated divalent aromatic heterocyclic groups containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms" is tetrahydroisoquinoline diyl (particularly 1,2,3,4-tetrahydroisoquinoline-2,6-diyl).

[0081] In this specification, the number of substituents in the case of “substituted” is one or more unless otherwise specified, and the types of substituents may be the same or different.

[0082] Next, preferred embodiments of the above general formula (I) will be described. A is preferably a ring selected from aromatic hydrocarbon rings (e.g., benzene rings), 5-6 membered aromatic heterocycles containing 1-3 atoms selected from oxygen, sulfur, and nitrogen, and cycloalkane rings (e.g., cyclobutane rings), more preferably a ring selected from benzene rings; pyridine rings; and cycloalkane rings (e.g., cyclobutane rings), and even more preferably a benzene ring.

[0083] Q is preferably a 5-6 member aromatic heterocycle (e.g., a pyrrole ring) containing 1-3 atoms selected from oxygen, sulfur, and nitrogen.

[0084] Substructure:

[0085] [ka]

[0086] Preferably, the formula is as follows:

[0087] [ka]

[0088] Therefore, Z 1 Preferably, is C and Z 2 Preferably, is C and Z 3 Preferably, =CR Z3 - and Z 4 Preferably, =CR Z4 - and Z 5 Preferably, =CR Z5 - and Q is preferably a pyrrole ring.

[0089] R Z3Preferably, the group is a hydrogen atom; a halogen atom (e.g., chlorine atom, bromine atom); a hydroxyl group; a cyano group; a hydroxycarbonyl group; an alkyl group (e.g., methyl, ethyl) which may be substituted with a group selected from halogen atoms (e.g., fluorine atom), hydroxyl groups, alkoxy groups, and cyano groups; a cycloalkyl group (e.g., cyclopropyl) which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups; an alkoxy group (e.g., methoxy) which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups; or an alkoxycal group which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups. A group selected from a bonyl group; more preferably a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group; a cycloalkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group; or an alkoxy group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group, and even more preferably an alkyl group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups; or an alkoxy group, particularly preferably an alkyl group, and even more preferably a methyl group or an ethyl group.

[0090] R Z4 and R Z5 Preferably, each is independently of the other a hydrogen atom; a halogen atom; a cyano group; an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; more preferably, each is independently of the other a hydrogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; and even more preferably, both are hydrogen atoms.

[0091] R aPreferably, is a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; more preferably, is a hydrogen atom; or an alkyl group; and even more preferably, is a hydrogen atom. R a’ Preferably, is a hydrogen atom; an alkyl group (e.g., methyl) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; more preferably, a hydrogen atom; or an alkyl group; and even more preferably, a hydrogen atom. R a’’ Preferably, is a hydrogen atom; a halogen atom (e.g., chlorine atom); an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; more preferably, is a hydrogen atom; a halogen atom; an alkyl group; or a cyano group; and even more preferably, is a cyano group.

[0092] Substructure:

[0093] [ka]

[0094] Preferably, the formula is (Ea) or (Ec):

[0095] [ka]

[0096] And, moreover,

[0097] [ka]

[0098] That is the case. R 9a and R 9bThese are, for example, alkyl groups (e.g., methyl) which may be independently substituted with a hydrogen atom; a halogen atom; a cyano group; or substituents selected from a halogen atom, a hydroxyl group, and a cyano group; and alkoxy groups (e.g., methoxy) which may be independently substituted with a halogen atom, a hydroxyl group, and a cyano group; preferably, groups selected from independently substituted with a hydrogen atom; a halogen atom; a cyano group; or alkyl groups (e.g., methyl) which may be independently substituted with substituents selected from a halogen atom, a hydroxyl group, and a cyano group; more preferably, alkyl groups which may be independently substituted with a hydroxyl group; particularly preferably, unsubstituted alkyl groups; and even more preferably, methyl groups.

[0099] L is preferably a group selected from divalent aromatic hydrocarbon groups (e.g., phenylene); divalent aliphatic heterocyclic groups (e.g., pyrrolidinediyl); divalent aromatic heterocyclic groups which may be partially hydrogenated (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofranziyl, benzoxazinediyl, benzothiophenediyl, tetrahydroquinolinediyl); alkylene groups; cycloalkylene groups; alkenylene groups; and alkylylene groups (e.g., -C≡C-, -C≡C-CH2-), where the group is , halogen atoms (e.g., fluorine atoms, chlorine atoms); hydroxyl groups; cyano groups; hydroxycarbonyl groups; alkyl groups (e.g., methyl) which may be substituted with groups selected from halogen atoms (e.g., fluorine atoms), hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups (e.g., methoxy) which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; more preferably substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups. A group selected from: an alkynyl group which may be substituted; a) a halogen atom, b) a hydroxyl group, c) a cyano group, d) an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group, and e) an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; and a divalent aromatic heterocyclic group containing one to two atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom which may be partially hydrogenated; wherein the aromatic heterocyclic group may be substituted with a substituent selected from a halogen atom, a hydroxyl group, a cyano group, and an oxo group, and more preferably an alkynylene group; a divalent aromatic hydrocarbon group which may be substituted with a substituent selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group; a divalent aliphatic heterocyclic group containing one nitrogen atom;A group selected from a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, which may be partially hydrogenated; an aromatic hydrocarbon group which may be substituted with an oxo group, and particularly preferably substituted with a substituent selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group; and a group selected from a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, which may be partially hydrogenated; more preferably a group selected from a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 halogen atoms; and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, particularly preferably a group selected from phenylene; pyridinediyl; and pyrazinediyl, which may be substituted with 1 to 2 halogen atoms; and even more preferably a group selected from phenylene; pyrazinediyl; which may be substituted with 1 to 2 halogen atoms.

[0100] In another embodiment, L is preferably a divalent aromatic hydrocarbon group (e.g., phenylene), which may be substituted with substituents selected from halogen atoms (e.g., fluorine atoms, chlorine atoms); hydroxyl groups; cyano groups; hydroxycarbonyl groups; alkyl groups (e.g., methyl) which may be substituted with groups selected from halogen atoms (e.g., fluorine atoms), hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups (e.g., methoxy) which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; more preferably a) halogen atom, b) hydroxyl group, c) cyano group, d) halogen atom, hydroxyl group and A divalent aromatic hydrocarbon group which may be substituted with substituents selected from an alkyl group which may be substituted with substituents selected from a cyano group, and a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a halogen atom, a hydroxyl group and a cyano group, particularly preferably a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a halogen atom, an alkyl group which may be substituted with a halogen atom, and an alkoxy group, even more preferably a divalent aromatic hydrocarbon group which may be substituted with 1 to 2 halogen atoms, and most preferably phenylene which may be substituted with 1 to 2 halogen atoms.

[0101] In another embodiment, L is preferably a divalent aromatic heterocyclic group which may be partially hydrogenated (e.g., thiophenediyl, pyridinediyl, tetrahydropyridinediyl, pyrazinediyl, benzofranziyl, benzooxazinediyl, benzothiophenediyl, tetrahydroquinolinediyl); alkylene group; cycloalkylene group; alkenylene group; and alkylylene group which may be -C≡C-, -C≡C-CH2-, wherein the group may be substituted with substituents selected from halogen atoms (e.g., fluorine atom, chlorine atom); hydroxyl group; cyano group; hydroxycarbonyl group; alkyl group which may be substituted with a group selected from halogen atoms (e.g., fluorine atom), hydroxyl group, alkoxy group and cyano group (e.g., methyl); and alkoxy group which may be substituted with a group selected from halogen atoms, hydroxyl group, alkoxy group and cyano group (e.g., methoxy); more preferably partially A divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, which may be hydrogenated, and which may be substituted with substituents selected from halogen, hydroxyl, cyano, and oxo groups; more preferably a group selected from a divalent aromatic heterocyclic group containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur atoms, which may be partially hydrogenated, and which may be substituted with oxo groups; particularly preferably a divalent aromatic hydrocarbon group substituted with substituents selected from halogen, alkyl groups which may be substituted with halogen atoms, and alkoxy groups; even more preferably a group selected from a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms, particularly preferably a group selected from pyridinediyl and pyrazinediyl, and even more preferably pyrazinediyl.

[0102] T is preferably a single bond, -CO-, -CO-NR 7c -, -NR 7cThe alkylene group (e.g., -CH2-) may be -CO- or -O-, or may be substituted with substituents selected from halogen atoms; hydroxyl groups; cyano groups; oxo groups; hydroxycarbonyl groups; alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; more preferably, a single bond; -CO-; -CO-NR 7c -;-NR 7c -CO-; or -O-, and particularly preferably -CO-NR 7c - is

[0103] M is preferably a single bond or -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c - ;Also, alkylene groups (e.g., -CH2-, -(CH2)2-, -(CH2)3-) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups;Alkynylene groups (e.g., -CH2-C≡C-) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups;Also, alkyl groups (e.g., -CH2-C≡C-) which may be substituted with substituents selected from a) halogen atoms, b) hydroxyl groups, c) cyano groups, d) oxo groups, e) halogen atoms, hydroxyl groups, alkoxy groups and cyano groups;And f)Alkoxy groups (e.g., piperidinediyl) which may be substituted with substituents selected from a) halogen atoms, hydroxyl groups, alkoxy groups and cyano groups;Divalent aliphatic heterocyclic groups (e.g., piperidinediyl) which may be substituted with substituents selected from a) 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; an alkynylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; and a divalent aliphatic heterocyclic group; a group which is more preferably a single bond or -R 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with a substituent selected from a hydroxyl group and a cyano group; an alkylene group which may be substituted with a substituent selected from a hydroxyl group and a cyano group; and a divalent aliphatic heterocyclic group which is a group which is particularly preferably an alkylene group which may be substituted with a single substituent selected from a hydroxyl group and a cyano group, and especially preferably -CH2- or -CH(CH3)-, and especially particularly preferably -CH2- or

[0104] [ka]

[0105] That is the case.

[0106] However, -LTM- is structured in whole or in part as -OO-, -SS-, or -NR. 7a -NR 7a -, -OS-, -SO-, -O-NR 7a -, -NR 7a -O-, -S-NR 7a - and -NR 7a The base selected from -S- is not indicated.

[0107] -LTM- is Preferably, L is an aromatic hydrocarbon group in which L may be substituted with 1-2 substituents selected from halogen atoms and alkyl groups; and a group selected from divalent aromatic heterocyclic groups containing 1-2 nitrogen atoms. T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2-, -(CH2)2-, or -CH(CH3)-, more, L is a phenylene group, pyridinediyl, and pyrazinediyl group, which may be substituted with one or two substituents selected from halogen atoms and alkyl groups. T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2-, -(CH2)2-, or -CH(CH3)-, More preferably, A phenylene group in which L may be substituted with 1-2 halogen atoms; and a pyrazinediyl group, T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2- or -CH(CH3)-, Particularly preferable, A phenylene group in which L may be substituted with 1-2 halogen atoms; and a pyrazinediyl group, T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2-, or

[0108] [ka]

[0109] That is the case.

[0110] Substructure:

[0111] [ka]

[0112] Preferably,

[0113] [ka]

[0114] That is the case.

[0115] Substructure:

[0116] [ka]

[0117] Preferably,

[0118] [ka]

[0119] Therefore, G is preferably N, and J is preferably N.

[0120] R 5 Preferably, it is a hydrogen atom.

[0121] R 6a and R 6bPreferably, the groups are selected independently from each other from a hydrogen atom; a halogen atom (e.g., a fluorine atom); a hydroxyl group; a cyano group; and an alkyl group (e.g., methyl) which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; more preferably, the groups are selected independently from each other from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; and even more preferably, the groups are selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group.

[0122] R 7a and R 7b Preferably, these are alkyl groups (e.g., methyl, ethyl) which may be independently substituted with hydrogen atoms or substituents selected from halogen atoms, hydroxyl groups, and cyano groups, and more preferably, alkyl groups which may be independently substituted with hydrogen atoms or hydroxyl groups.

[0123] R 7c Preferably, it is a hydrogen atom. R 7d Preferably, is an alkyl group (e.g., methyl) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups, and more preferably is an alkyl group.

[0124] R 7r Preferably, is an alkylene group (e.g., -CH2-, -(CH2)2-, -(CH2)3-) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups, and more preferably is an alkylene group.

[0125] R 8a and R 8b Preferably, these are groups independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, and a cyano group, and more preferably, all of them are hydrogen atoms.

[0126] R 10a and R 10bPreferably, the hydrogen atoms are independent of each other;-N(R 7c )-CO-OR 7d ; and alkyl groups (e.g., methyl); wherein the alkyl group is a substituent selected from halogen atoms; hydroxyl groups; cyano groups; alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; alkoxycarbonyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups (e.g., methoxycarbonyl, t-butoxycarbonyl);-CO-N(R 7a )(R 7b ); and hydroxycarbonyl groups; may be substituted with substituents selected from these, more preferably R 10a hydrogen atoms; as well as halogen atoms, hydroxyl groups, cyano groups, -NH-CO-OR 7d , -CO-N(R 7a )(R 7b A group selected from an alkyl group which may be substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group, and R 10b is a hydrogen atom, and more preferably R 10a is a hydrogen atom; and -NH-CO-OR 7d , -CO-N(R 7a )(R 7b A group selected from R, which may be substituted with substituents selected from a cyano group, an alkoxycarbonyl group, and a hydroxycarbonyl group; and an alkyl group. 10b is a hydrogen atom, and particularly preferably R 10a R is an alkyl group which may be substituted with one alkoxycarbonyl group, and 10b is a hydrogen atom, and more preferably R 10a This is a methyl group which may be substituted with one substituent selected from a tert-butoxycarbonyl group and a methoxycarbonyl group, Preferably, it is a methyl group substituted with a methoxycarbonyl group.

[0127] R 11Preferably, is an alkyl group (e.g., methyl) which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; more preferably, is an alkyl group; and particularly preferably is a methyl group.

[0128] The following are examples of compounds represented by general formula (I): [Compound IA] A is a ring selected from 5-6 member aromatic heterocycles and cycloalkane rings containing 1-3 atoms selected from aromatic hydrocarbon rings, oxygen, sulfur, and nitrogen. Substructure:

[0129] [ka]

[0130] However, the following formula:

[0131] [ka]

[0132] Show, R a However, it represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; R a’ However, hydrogen atoms; halogen atoms; hydroxyl groups; cyano groups; alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; alkoxycarbonyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; or -CO-N(R 7a )(R 7b ) indicates, R a’’However, hydrogen atoms; halogen atoms; cyano groups; alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; alkoxycarbonyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; or -CO-N(R 7a )(R 7b ) indicates, R Z3 but, This indicates a group selected from: hydrogen atom; halogen atom; hydroxyl group; cyano group; hydroxycarbonyl group; alkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; cycloalkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxy group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; R Z4 and R Z5 These independently represent a group selected from: a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; Substructure:

[0133] [ka]

[0134] However, the following formula (Ea) or (Ec):

[0135] [ka]

[0136] Show, Substructure:

[0137] [ka]

[0138] but,

[0139] [ka]

[0140] Show, Substructure:

[0141] [ka]

[0142] but,

[0143] [ka]

[0144] Show, L is a group selected from: a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkylene group. The group may be substituted with substituents selected from halogen atoms; hydroxyl groups; cyano groups; hydroxycarbonyl groups; alkyl groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups. T has a single bond, -CO-, and -CO-NR 7c -, -NR 7c It indicates -CO- or -O-, A halogen atom; a hydroxyl group; a cyano group; an oxo group; a hydroxycarbonyl group; an alkyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; Is M a single bond? -O-;-S-;-NR 7a -;-CO-;-SO-;-SO2-;-CO-NR 7c -;-NR 7c -CO-;-SO2-NR 7c -;-NR 7c -SO2-;-NR 7a -CO-NR 7b -;-(OCH2CH2) m -;-OR 7r -;-R 7r -O-;-SR 7r -;-R 7r -S-;-NR 7a -R 7r -;-R 7r -NR 7a -;-CO-NR 7c -R 7r -;-R 7r -CO-NR 7c -; and alkylene groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; alkynylene groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and divalent aliphatic heterocyclic groups which may be substituted with substituents selected from a) halogen atoms, b) hydroxyl groups, c) cyano groups, d) oxo groups, e) alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups, and f) alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; R 5 That is a hydrogen atom, R 6a and R 6bThese are groups that are independently selected from a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7c That is a hydrogen atom, R 8a and R 8b These are groups that are independently selected from hydrogen atoms; halogen atoms; hydroxyl groups; and cyano groups. R 9a and R 9b However, each group is independently selected from a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; R 10a and R 10b These are independent of each other, hydrogen atoms;-N(R 7c )-CO-OR 7d The substituents selected from ; and alkyl groups; are shown. The alkyl group in question is Halogen atom; hydroxyl group; cyano group; alkoxy group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; -CO-N(R 7a )(R 7b ); and hydroxycarbonyl groups; may be substituted with substituents selected from these, Compound (I).

[0145] [Compound IB] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring. Substructure:

[0146] [ka]

[0147] However, the following formula:

[0148] [ka]

[0149] Show, R a However, it represents an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R a’ However, it represents an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R a’’ However, it represents a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group. R Z3 However, it represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; R Z4 and R Z5 These independently represent a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; Substructure:

[0150] [ka]

[0151] However, the following equation (Ea):

[0152] [ka]

[0153] Show, Substructure:

[0154] [ka]

[0155] but,

[0156] [ka]

[0157] Show, Substructure:

[0158] [ka]

[0159] but,

[0160] [ka]

[0161] Show, L is a group selected from: an alkynyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a) halogen atom, b) hydroxyl group, c) cyano group, d) alkyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups, and e) alkoxy group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; and a divalent aromatic heterocyclic group containing one to two atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may be partially hydrogenated. The aromatic heterocyclic group may be substituted with substituents selected from halogen atoms, hydroxyl groups, cyano groups, and oxo groups. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; Is M a single bond? -R 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; an alkynylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; and a divalent aliphatic heterocyclic group; a group selected from these, R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7r This represents an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, these alkyl groups may be substituted with substituents selected independently from halogen atoms, hydroxyl groups, and cyano groups. R 10a hydrogen atoms; as well as halogen atoms, hydroxyl groups, cyano groups, -NH-CO-OR7d ,-CO-N(R 7a )(R 7b ), an alkyl group which may be substituted with substituents selected from alkoxycarbonyl groups and hydroxycarbonyl groups; R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0162] [Compound IC] A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring. Substructure:

[0163] [ka]

[0164] However, the following formula:

[0165] [ka]

[0166] Show, R a However, it represents a hydrogen atom; or an alkyl group. R a’ However, it represents a hydrogen atom; or an alkyl group. R a’’ However, it represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group. R Z3 However, it represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxyl group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 Each independently represents a hydrogen atom; or an alkyl group; Substructure:

[0167] [ka]

[0168] However, the following equation (Ea):

[0169] [ka]

[0170] Show, Substructure:

[0171] [ka]

[0172] but,

[0173] [ka]

[0174] Show, Substructure:

[0175] [ka]

[0176] but,

[0177] [ka]

[0178] Show, L is a group selected from: an alkynyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a) halogen atom, b) hydroxyl group, c) cyano group, d) alkyl group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups, and e) alkoxy group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; and a divalent aromatic heterocyclic group containing one to two atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may be partially hydrogenated. The aromatic heterocyclic group may be substituted with substituents selected from halogen atoms, hydroxyl groups, cyano groups, and oxo groups. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; Is M a single bond? -R 7r -O-;-R 7r -NR 7a -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; an alkynylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; and a divalent aliphatic heterocyclic group; a group selected from these, R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7dThis represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7r This represents an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, these alkyl groups may be substituted with substituents selected independently from halogen atoms, hydroxyl groups, and cyano groups. R 10a hydrogen atoms; as well as halogen atoms, hydroxyl groups, cyano groups, -NH-CO-OR 7d ,-CO-N(R 7a )(R 7b ), an alkyl group which may be substituted with substituents selected from alkoxycarbonyl groups and hydroxycarbonyl groups; R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0179] [Compound ID] A is a benzene ring, Substructure:

[0180] [ka]

[0181] However, the following formula:

[0182] [ka]

[0183] Show, R a However, it shows a hydrogen atom. R a’ However, it represents a hydrogen atom; or an alkyl group. R a’’ However, it represents a hydrogen atom; a halogen atom; an alkyl group; or a cyano group. R Z3 However, it represents a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a halogen atom or a hydroxyl group; a cycloalkyl group; or an alkoxy group; R Z4 and R Z5 Each independently represents a hydrogen atom; or an alkyl group; Substructure:

[0184] [ka]

[0185] However, the following equation (Ea):

[0186] [ka]

[0187] Show, Substructure:

[0188] [ka]

[0189] but,

[0190] [ka]

[0191] Show, Substructure:

[0192] [ka]

[0193] but,

[0194] [ka]

[0195] Show, L is a group selected from: a divalent aromatic hydrocarbon group which may be substituted with substituents selected from halogen atoms, alkyl groups which may be substituted with halogen atoms, and alkoxy groups; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms; T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; M is an alkylene group which may be substituted with a hydroxyl group and a cyano group. R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 7r This represents an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9bHowever, these alkyl groups may be substituted with substituents selected independently from halogen atoms, hydroxyl groups, and cyano groups. R 10a However, it is an alkyl group that may be substituted with an alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0196] [Compound IE] A is a benzene ring, Substructure:

[0197] [ka]

[0198] However, the following formula:

[0199] [ka]

[0200] Show, R a However, it shows a hydrogen atom. R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it represents an alkyl group or alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups, R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0201] [ka]

[0202] However, the following equation (Ea):

[0203] [ka]

[0204] Show, Substructure:

[0205] [ka]

[0206] but,

[0207] [ka]

[0208] Show, Substructure:

[0209] [ka]

[0210] but,

[0211] [ka]

[0212] Show, L is a group selected from a divalent aromatic hydrocarbon group which may be substituted with one or two substituents selected from a halogen atom, an alkyl group which may be substituted with one to three halogen atoms, and an alkoxy group; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains one or two atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c-CO-; or -O-; M is an alkylene group which may be substituted with one substituent selected from a hydroxyl group and a cyano group. R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7r This represents an alkylene group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, each alkyl group may be independently substituted with one substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 10a However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0213] [Compound IF] A is a benzene ring, Substructure:

[0214] [ka]

[0215] However, the following formula:

[0216] [ka]

[0217] Show, R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it indicates an alkyl group; or an alkoxy group; R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0218] [ka]

[0219] However, the following equation (Ea):

[0220] [ka]

[0221] Show, Substructure:

[0222] [ka]

[0223] but,

[0224] [ka]

[0225] Show, Substructure:

[0226] [ka]

[0227] but,

[0228] [ka]

[0229] Show, L is a group selected from a divalent aromatic hydrocarbon group in which L may be substituted with 1 to 2 substituents selected from halogen atoms and alkyl groups, and a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms. T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2-, -(CH2)2-, or -CH(CH3)-, R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, they are alkyl groups independently of each other. R 10a This alkyl group may be substituted with one alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 is an alkyl group. Compound (I).

[0230] [Compound IG] A is a benzene ring, Substructure:

[0231] [ka]

[0232] However, the following formula:

[0233] [ka]

[0234] Show, R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it indicates an alkyl group; or an alkoxy group; R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0235] [ka]

[0236] However, the following equation (Ea):

[0237] [ka]

[0238] Show, Substructure:

[0239] [ka]

[0240] but,

[0241] [ka]

[0242] Show, Substructure:

[0243] [ka]

[0244] but,

[0245] [ka]

[0246] Show, L is a group selected from a phenylene group; a pyridinediyl group; and a pyrazinediyl group; which may be substituted with one or two substituents selected from halogen atoms and alkyl groups. T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2-, -(CH2)2-, or -CH(CH3)-, R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, they are alkyl groups independently of each other. R 10a This alkyl group may be substituted with one alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 is an alkyl group. Compound (I).

[0247] [Compound IH] A is a benzene ring, Substructure:

[0248] [ka]

[0249] However, the following formula:

[0250] [ka]

[0251] Show, R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it indicates an alkyl group; or an alkoxy group; R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0252] [ka]

[0253] However, the following equation (Ea):

[0254] [ka]

[0255] Show, Substructure:

[0256] [ka]

[0257] but,

[0258] [ka]

[0259] Show, Substructure:

[0260] [ka]

[0261] but,

[0262] [ka]

[0263] Show, L is a group selected from a phenylene group, which may be substituted with one or two substituents selected from halogen atoms and alkyl groups; and a pyrazinediyl group. T, -CO-NR 7c - and R 7c That is a hydrogen atom, M is -CH2- or -CH(CH3)-, R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, they are alkyl groups independently of each other. R 10a is an alkyl group substituted with one alkoxycarbonyl group, R 10b That is a hydrogen atom, R 11 is an alkyl group. Compound (I).

[0264] [Compound II] A is a benzene ring, Substructure:

[0265] [ka]

[0266] However, the following formula:

[0267] [ka]

[0268] Show, R aHowever, it shows a hydrogen atom. R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it represents an alkyl group or alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups, R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0269] [ka]

[0270] However, the following equation (Ea):

[0271] [ka]

[0272] Show, Substructure:

[0273] [ka]

[0274] but,

[0275] [ka]

[0276] Show, Substructure:

[0277] [ka]

[0278] but,

[0279] [ka]

[0280] Show, L is a divalent aromatic hydrocarbon group which may be substituted with one or two substituents selected from a halogen atom, an alkyl group which may be substituted with one to three halogen atoms, and an alkoxy group. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; M is an alkylene group which may be substituted with one substituent selected from a hydroxyl group and a cyano group. R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7r This represents an alkylene group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, each alkyl group may be independently substituted with one substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 10aHowever, it is an alkyl group that may be substituted with one alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0281] [Compound IJ] A is a benzene ring, Substructure:

[0282] [ka]

[0283] However, the following formula:

[0284] [ka]

[0285] Show, R a However, it shows a hydrogen atom. R a’ However, it shows a hydrogen atom. R a’’ However, it shows a cyano group, R Z3 However, it represents an alkyl group or alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups, R Z4 This represents a hydrogen atom. R Z5 This represents a hydrogen atom. Substructure:

[0286] [ka]

[0287] However, the following equation (Ea):

[0288] [ka]

[0289] Show, Substructure:

[0290] [ka]

[0291] but,

[0292] [ka]

[0293] Show, Substructure:

[0294] [ka]

[0295] but,

[0296] [ka]

[0297] Show, L is a divalent aromatic heterocyclic group containing 1 to 2 nitrogen atoms. T is a single bond;-CO-;-CO-NR 7c -;-NR 7c -CO-; or -O-; M is an alkylene group which may be substituted with one substituent selected from a hydroxyl group and a cyano group. R 6a and R 6b These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxyl group, and a cyano group. R 7a and R 7b However, each alkyl group may be independently substituted with a hydrogen atom or 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7c This represents a hydrogen atom. R 7d This represents an alkyl group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 7r This represents an alkylene group which may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R 8a and R 8b All of them are hydrogen atoms, R 9a and R 9b However, each alkyl group may be independently substituted with one substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R 10a However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. R 10b That is a hydrogen atom, R 11 This alkyl group may be substituted with 1 to 3 substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Compound (I).

[0298] Specific examples of compounds represented by formula (I) include, for example, the compounds of Examples 1 to 126 described below, preferably the compounds of Examples 1, 11, 15, 26, 43, 45, 46, 47, 50, 53, 63, 64, 65, 69, 70, 71, 74, 85, 92, 97, 98, 99, 100, 102, 103, 105, 106, 107, 108, 109, 110, 118, 127 and 148, more preferably the compounds of Examples 1, 11, 26, 43, 47, 53, 63, 64, 65, 69, 71, 74, 92, 102, 103, 105, 106, 107, 108, 109 and 110, and even more preferably the compounds of Examples 1, 47, 74 and 106.

[0299] In the present invention, "medically acceptable salt" is not particularly limited as long as it is a medicinally acceptable salt, and includes salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, salts with inorganic bases, and salts with organic bases. Furthermore, hydrates, which are water-containing salts, and solvates, which are solvent-containing salts, are also included in the definition of medicinally acceptable salts in the present invention.

[0300] "Medically acceptable" as used herein means that a substance is generally safe and harmless, and is otherwise desirable even if it is not biologically desirable, and is useful in preparing pharmaceutical compositions that are useful not only for human medicinal use but also for veterinary use.

[0301] The compounds of the present invention can be produced by the following methods A to F. These methods and processes may be combined with each other, but the production methods are not limited to these.

[0302] Below, R 10 is R 10a or R 10b Show, R 10a or R 10b One example is the case where a hydrogen atom is involved, 10a , R 10b Even in the case of alkyls where both are substituted, the following method applies. (R10a , R 10b (This is synonymous with the above.)

[0303] (Method A) (1) The manufacturing method described herein is suitable for producing an intermediate of a compound represented by general formula (I) in which ring E is represented by the above general formula (Ea), G is a nitrogen atom, and J is a nitrogen atom, i.e., the compound (A-1) described below.

[0304] [ka]

[0305] (In the formula, each symbol has the same meaning as above.) Process A-1 Compound (1-2) can be derived from compound (1-1) according to known methods (e.g., J.Med.Chem. 1973, 16, 214-219). Process A-2 Compound (1-3) is obtained by acylation of compound (1-2). The reaction proceeds using a base in a suitable solvent, usually at -20°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of acylation agents include trifluoroacetic anhydride, acetic anhydride, propanoic anhydride, and acetyl chloride. Examples of bases include triethylamine and pyridine. Examples of solvents include tetrahydrofuran, dichloromethane, toluene, and 1,4-dioxane. Process A-3 Compounds (1-4) are obtained by thioamidating compound (1-3). The thioamidation reaction proceeds using a sulfurizing agent in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of sulfurizing agents include Lawson's reagent and phosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane. Process A-4 Compounds (1-5) are obtained by the reaction of compound (1-4) with hydrazine. The reaction with hydrazine proceeds using hydrazine monohydrate in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 1 and 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. Process A-5 Compounds (1-6) are R 10 The compounds are obtained by converting carboxylic acid derivatives (1-10) having substituents to acid halides using a halogenating agent, and then reacting them with compounds (1-5). The reaction proceeds with a base in a suitable solvent, usually from 0°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 1 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process A-6 Compounds (1-7) are obtained by the cyclization reaction of compounds (1-6). This reaction proceeds in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 1 and 24 hours. Examples of solvents include 2-propanol, 1-butanol, and tetrahydrofuran. Process A-7 Compounds (1-8) are obtained by the deprotection reaction of compounds (1-7). The reaction proceeds using an acid in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 1 and 24 hours. Examples of acids include hydrochloric acid and trifluoroacetic acid. Examples of solvents include ethyl acetate, 1,4-dioxane, tetrahydrofuran, dichloromethane, and chloroform. Process A-8 Compounds (1-9) are obtained by the cyclization reaction of compounds (1-8). The reaction proceeds using a coupling agent in the presence of a suitable base, in a suitable solvent, at 0°C to the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 1 to 24 hours. Examples of coupling agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy[1.3.5]triazine-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM), and 2-chloro-1-methylpyridinium iodide. Suitable solvents include methanol, N,N-dimethylformamide, chloroform, dichloromethane, and tetrahydrofuran. The reaction may also be accelerated by adding 1-hydroxybenzotriazole (HOBt). Suitable bases include triethylamine, N,N-diisopropylethylamine, and pyridine. Process A-9 Compound (A-1) is obtained by halogenation of compounds (1-9). The reaction proceeds using a halogenating agent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 1 and 24 hours. Examples of halogenating agents include phosphoryl chloride.

[0306] (2) The manufacturing method described herein is suitable for producing an intermediate of a compound represented by general formula (I) in which ring E is represented by the above general formula (Ec), G is a nitrogen atom, and J is a nitrogen atom, i.e., the compound (A-2) described below.

[0307] [ka]

[0308] (In the formula, each symbol has the same meaning as above.) Compound (A-2) can be derived from compound (2-1) according to known methods (e.g., J.Med.Chem.2016,59,1426).

[0309] (3) The manufacturing method described herein is suitable for producing intermediates of compounds represented by general formula (I) in which G is a carbon atom and J is an oxygen atom, i.e., the compound (A-3) described below.

[0310] [ka]

[0311] (In the formula, B 1 is a boronic acid or a boronic acid ester which may have substituents, Z A P is a halogen atom. A (The symbol indicates a protecting group, and each other symbol has the same meaning as above.) B in the formula 1 Boronic acid esters that may have substituents include pinacolateborone, neopentylglycolateborone, and Z A The halogen atoms in this formula refer to chlorine, bromine, and iodine atoms. A The protecting group protects the carboxyl group and is not particularly limited as long as it is one that can be used to obtain compound (3-7). Examples include alkyl groups (specifically methyl and ethyl). Compound (A-3) can be derived from compound (3-1) according to known methods (e.g., WO2012 / 075383).

[0312] (Method B) (1) The intermediate of the compound represented by general formula (I), i.e., the compound (B-1) below, can be synthesized by the following method.

[0313] [ka]

[0314] (In the formula, Z B(The symbol indicates a chlorine atom or a hydroxyl group, and the other symbols have the same meaning as above.) Process B-1 Compound (B-1) is obtained by a coupling reaction between compound (A-4) and the boronic acid derivative (4-1). The reaction preferably proceeds in a suitable solvent in the presence of a palladium catalyst, a phosphine ligand, and a base, at temperatures ranging from 0°C to heated, particularly from room temperature to the boiling point of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually between 1 and 24 hours. Examples of palladium catalysts include palladium(II) acetate, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(O), or their chloroform adducts. Examples of phosphine ligands include triphenylphosphine, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-(dicyclohexylphosphino)-2,6-diisopropoxy-1,1'-biphenyl, and 2-di-t-butylphosphino-2'-4'-6'-triisopropylbiphenyl. Examples include 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl, 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl, tri-ortho-tolylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 2-(di-t-butylphosphino)-1,1-binaphthyl, tri-t-butylphosphine, and tri-t-butylphosphonium tetrafluoroborate.Reagents in which a palladium catalyst and a phosphine ligand form a complex may also be used, for example, tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlorobis(triphenylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), bis(tri-t-butylphosphine)palladium(0), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- Examples include triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-t-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, and [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II). Examples of bases include t-butoxysodium, potassium acetate, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium bicarbonate, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, dicyclohexylethylamine, potassium fluoride, and cesium fluoride. Examples of solvents include ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; alcohol-based solvents such as methanol, ethanol, propanol, and butanol; N,N-dimethylformamide; or mixed solvents of these organic solvents with water.

[0315] (2) The manufacturing method described herein is suitable for producing intermediates of compounds represented by general formula (I) in which G is a nitrogen atom and J is a nitrogen atom, i.e., the compound (B-2) described below.

[0316] [ka]

[0317] (In the formula, each symbol has the same meaning as above.) Process B-2 Compound (5-2) is R 10 The compound (5-1) is obtained by converting the carboxylic acid derivative (1-10) having the substituent to an acid halide with a halogenating agent, and then reacting it with the compound (5-1). The reaction proceeds with a base in a suitable solvent, usually from -20°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene.

[0318] Process B-3 Compound (5-3) is obtained by the deprotection and cyclization reactions of compound (5-2). The deprotection reaction proceeds using an acid in a suitable solvent, usually from 0°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Examples of acids include trifluoroacetic acid and hydrochloric acid. Examples of solvents include dichloromethane, chloroform, and tetrahydrofuran. This reaction can also be carried out using only acid. The cyclization reaction proceeds using an acid in a suitable solvent, usually from room temperature to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Examples of acids include trifluoroacetic acid and acetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol.

[0319] Process B-4 Compound (B-2) can be obtained from compound (5-3) by the following two methods. The first reaction can be obtained by hydrazine addition, acylation, and cyclization reactions. The reaction with hydrazine proceeds using a base and hydrazine in a suitable solvent, usually at 0°C to room temperature. Examples of bases include sodium hydride, t-sodium butoxy, and t-potassium butoxy. The acylation reaction proceeds using an acyling agent in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Examples of acyling agents include trifluoroacetic anhydride, acetic anhydride, and propanoic anhydride. Examples of solvents include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dichloromethane. The above reactions can also be carried out using acylhydrazides instead of hydrazine and acid chlorides or acid anhydrides. Examples of acylhydrazides include acetylhydrazine. Cyclization reactions proceed using an acid in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is typically 0.5 to 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol. This reaction also proceeds after the addition of hydrazine using the corresponding orthoester, in a suitable solvent, usually at room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is typically 0.5 to 24 hours. Examples of orthoesters include 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

[0320] The second product can be obtained by converting the amide group to a thioamide group, followed by hydrazine addition, acylation, and cyclization reactions. The thioamidation reaction proceeds using a sulfurizing agent in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Examples of sulfurizing agents include Lawson's reagent and phosphorus pentasulfide. Examples of solvents include 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane. The hydrazine addition reaction proceeds using hydrazine in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 1 to 24 hours. Examples of solvents include tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. The acylation reaction proceeds using an acyling agent in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 1 and 24 hours. Examples of acylating agents include trifluoroacetic anhydride, acetic anhydride, and propanoic anhydride. Instead of using hydrazine and acid chlorides or acid anhydrides, the above reaction can also be carried out using acyl hydrazides. Examples of acyl hydrazides include acetylhydrazine. Examples of solvents include tetrahydrofuran and N,N-dimethylformamide. The cyclization reaction proceeds using an acid in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of acids include acetic acid and trifluoroacetic acid. Examples of solvents include tetrahydrofuran, N,N-dimethylformamide, 1-butanol, and 2-propanol. This reaction proceeds using the corresponding orthoester after the addition of hydrazine, in a suitable solvent, usually from room temperature to reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of orthoester compounds include 1,1,1-triethoxyethane and 1,1,1-trimethoxypentane. Examples of solvents include toluene and tetrahydrofuran.

[0321] (3) Among the compounds represented by general formula (I), the intermediate of a compound in which G is a nitrogen atom and J is a nitrogen atom, i.e., the compound (B-2) shown below, can also be synthesized by the following method.

[0322] [ka]

[0323] (In the formula, P B (The symbol indicates a protecting group, and the other symbols are equivalent to those above.) P in the formula B The protector is not particularly limited as long as it protects the carboxyl group. Examples include alkyl groups (specifically methyl, ethyl, t-butyl, etc.) and aralkyl groups (benzyl, etc.). Compound (B-2) can also be synthesized from compound (6-1) according to known methods (e.g., methods described in WO1993 / 007129 and WO1998 / 011111).

[0324] (4) The manufacturing method described herein involves R of the compound represented by general formula (I). 10 ga-N(R 7c )-CO-OR 7d It is suitable for producing intermediates of the compound, namely the following compounds (B-3) and (B-4). (R 7c and R 7d (This is synonymous with the above.)

[0325] [ka]

[0326] (In the formula, each symbol has the same meaning as above.) Process B-8 Compound (B-3) is synthesized from compound (7-1) according to a known method (e.g., Japanese Patent Publication No. 7-17941), and the corresponding acid halide (Cl-CO-OR 7d ) or acid anhydride (R 7d O-CO-O-CO-OR 7dIt is obtained by reacting with ). The reaction proceeds using a base in a suitable solvent, usually from -20°C to the reflux temperature of the solvent. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 30 minutes to 24 hours. Examples of bases include triethylamine, N,N-diisopropylethylamine, and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, pyridine, and toluene. In this reaction, the base used can also be used as the solvent.

[0327] Process B-9 Compound (B-4) is obtained by alkylating compound (B-3). The alkylation reaction proceeds in a suitable solvent using a base and an alkylating agent such as an alkyl halide, usually from 0°C to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent and reaction temperature used, but is usually from 10 minutes to 24 hours. Examples of bases include inorganic bases such as sodium hydride, potassium hydroxide, and potassium carbonate, and alkoxides such as potassium t-butoxide. Examples of solvents include N,N-dimethylformamide, tetrahydrofuran, and dimethyl sulfoxide.

[0328] (5) The manufacturing method described herein involves R of the compound represented by general formula (I). 10 It is suitable for producing intermediates of compounds in which the group is a hydroxyl group, namely the compound (B-5) described below.

[0329] [ka]

[0330] (In the formula, each symbol has the same meaning as above.) Compound (B-5) can be derived from compound (8-1) according to known methods (e.g., US4959361).

[0331] (6) The manufacturing method described herein involves R of the compound represented by general formula (I). 10 ga-(CH2)k -CO-N(R 7a )(R 7b It is suitable for producing intermediates of compounds that are ), namely the following compound (B-6).

[0332] [ka]

[0333] (In the formula, P C represents a hydrogen atom or protecting group, and k represents an integer from 1 to 6. Each symbol has the same meaning as described above. P in the formula C The protecting group is not particularly limited as long as it protects the carboxyl group. Examples include alkyl groups (specifically methyl, ethyl, t-butyl, etc.) and aralkyl groups (benzyl, etc.). Process B-13 Compound (9-2) has the protecting group P of compound (9-1). C It is obtained by removing P C If it is a hydrogen atom, this step can be omitted. The conditions for deprotection are, P C It is not particularly limited as long as it is used for deprotection, for example, P C If the compound is methyl or ethyl, methods using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol-based solvent and water are used. If the compound is t-butyl, methods using an acid such as hydrochloric acid or trifluoroacetic acid are used. Note that P C If the substance is benzyl, substituted benzyl, benzyloxymethyl, etc., a method using catalytic hydrogenation can be cited. Process B-14 Compound (B-6) corresponds to compound (9-2) in terms of R 7a , R 7b It is obtained by condensing with an amine containing [a specific compound]. The reaction proceeds using a condensing agent in the presence of a suitable base, in a suitable solvent, at 0°C to the reflux temperature of the solvent. The reaction time and the condensing agent, solvent, reaction accelerator, and base used are the same as in step A-8.

[0334] (7) The manufacturing method described herein is suitable for producing intermediates of compounds represented by general formula (I) in which ring E is represented by the above general formula (Eb), G is a nitrogen atom, and J is a nitrogen atom, i.e., the following compound (B-7).

[0335] [ka]

[0336] (In the formula, P D The symbol indicates a protecting group, and each symbol has the same meaning as above. P in the formula D The group is not particularly limited as long as it protects the amide group and yields the compound (10-9). Examples include the 4-methoxybenzyl group and the 2,4-dimethoxybenzyl group. Compound (B-7) can be synthesized from compound (10-1) according to the methods described in SYNLETT, 2008, 15, 2360-2364 and J. Org. Chem., 2009, 74, 4975-4981.

[0337] (8) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, R 9a The intermediate of the compound exhibiting cyanomethyl, i.e., the compound (B-8) below, can also be produced, for example, by the following manufacturing method.

[0338] [ka]

[0339] (The symbols in the formula have the same meaning as above.) Process B-24 Compound (11-2) is obtained by reacting compound (11-1) with a mixture of magnesium acetate dihydrate, acetic acid, acetic anhydride, and concentrated sulfuric acid at room temperature for an appropriate amount of time. Process B-25 Compound (11-3) is obtained by the reaction of compound (11-2) with a base. The reaction proceeds in a suitable solvent, usually at 0°C to room temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of bases include aqueous sodium hydroxide solution and aqueous potassium hydroxide solution. Examples of solvents include methanol, ethanol, tetrahydrofuran, and 1,4-dioxane. Process B-26 Compound (B-8) is obtained by converting the hydroxyl group of compound (11-3) to a leaving group and then substituting it with a cyano group (cyanoization). The conversion to a leaving group proceeds in a suitable solvent, usually at 0°C to room temperature, using a protecting agent and a base. Examples of protecting agents include p-toluenesulfonyl chloride and mesyl chloride. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 1 to 24 hours. Examples of bases include triethylamine and N,N-diisopropylethylamine. Examples of solvents include dichloromethane and tetrahydrofuran. The cyanation reaction proceeds in a suitable solvent, usually at 0°C to the reflux temperature of the solvent, using a cyanating agent. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 1 to 24 hours. Examples of cyanating agents include sodium cyanide and trimethylsilyl cyanide. Examples of solvents include dimethyl sulfoxide, acetonitrile, and tetrahydrofuran. When using trimethylsilyl cyanide, tetrabutylammonium fluoride is used.

[0340] (9) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, R 9a An intermediate of a compound exhibiting an alkyl group having 1 to 6 carbon atoms substituted with a cyano group, i.e., the compound (B-9) below, can also be produced by, for example, the following manufacturing method.

[0341] [ka]

[0342] (In the formula, k represents any integer from 1 to 6. Other symbols have the same meaning as above.) Process B-27 Compound (B-9) is obtained by cyanating compound (12-1). The reaction conditions are the same as those for step B-26 described above.

[0343] (10) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, R 9a An intermediate of a compound exhibiting a cyano group, i.e., the compound (B-10) shown below, can be produced, for example, by the following manufacturing method.

[0344] [ka]

[0345] (In the formula, each symbol has the same meaning as above.) Process B-28 Compound (13-1) is obtained by oxidizing compound (11-3). Reaction conditions include, for example, reacting a mixture of compound (11-3), manganese dioxide, and dichloromethane at room temperature for an appropriate amount of time. Process B-29 Compound (B-10) is obtained by cyanating compound (13-1). Reaction conditions include, for example, reacting a mixture of hydroxylamine hydrochloride and dimethyl sulfoxide under heating for an appropriate amount of time.

[0346] (11) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, R 9a The intermediate of a compound in which a hydrogen atom is present, i.e., the compound (B-11) shown below, can be produced, for example, by the following manufacturing method.

[0347] [ka]

[0348] (In the formula, each symbol has the same meaning as above.) Process B-30 Compound (14-1) is obtained by oxidizing compound (13-1). The reaction proceeds using an oxidizing agent in a suitable solvent, usually at 0°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 0.5 to 24 hours. Examples of oxidizing agents include hydrogen peroxide, t-butyl hydroperoxide, sodium chlorite, and potassium permanganate. Examples of solvents include methanol, acetonitrile, and water. The reaction proceeds, for example, by adding 35% hydrogen peroxide solution and sodium chlorite solution to a mixture of acetonitrile and sodium dihydrogen phosphate aqueous solution at 0°C to room temperature. Process B-31 Compound (B-11) is obtained by decarboxylating compound (14-1). Reaction conditions include, for example, reacting in copper-containing quinoline at 150°C.

[0349] (Method C) (1) The intermediate of the compound represented by general formula (I), i.e., the compound (C-1) below, can be produced, for example, by the following manufacturing method.

[0350] [ka]

[0351] (In the formula, Z A indicates a halogen atom, Z D B indicates an activating group of the hydroxyl group, 2 (The symbol represents a hydrogen atom, an amine, an olefin, an acetylene, a thiol, an alcohol, a boronic acid, or a boronic acid ester which may have substituents.) Other symbols are as defined above. Z in the formula A The halogen atoms in this context refer to chlorine, bromine, and iodine atoms. DExamples of activating groups for the hydroxyl group shown in the formula include sulfonyl groups such as trifluoromethanesulfonyl and toluenesulfonyl. 2 Boronic acid esters that may have substituents include pinacolate boron and neopentyl glycolate boron. Process C-1 The hydroxyl group of compound (16-2) is activated by the activating group OZ D This is a process of converting to [a specific substance]. The reaction preferably proceeds in the presence of a base, in a suitable solvent, at a temperature of about -50 to 50°C, and especially from 0°C to room temperature. As activating reagents, activated sulfonic acid derivatives such as trifluoromethanesulfonic anhydride, 1-(trifluoromethanesulfonyl)imidazole, and toluenesulfonyl chloride are used. This reaction can also be carried out by using a sulfonic acid in combination with a coupling agent. Examples of bases include triethylamine, pyridine, and lutidine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process C-2 Compound (C-1) is obtained by reacting compound (16-1) or compound (16-3) with compound (16-4). Compound (16-1) or compound (16-3), and P C OC(O)-LB 2 (In the formula, L, P C Compound (C-1) is obtained by a coupling reaction with an arylboronic acid derivative represented by an amine, olefin, acetylene, thiol, alcohol, LB(OH)2 or its ester (wherein L is as defined above). The palladium catalyst, phosphine ligand, reagent formed by the complex formation of the palladium catalyst and phosphine ligand, base and solvent used are the same as in step B-1. Furthermore, if L is an aryl compound having 6 to 12 carbon atoms, a heteroaryl compound with 5 to 12 ring atoms, an olefin, or an acetylene, compound (C-1) can also be obtained by a coupling reaction of compound (16-1) or compound (16-3) with an organometallic salt of L (e.g., tin, zinc, copper, etc.) or an alkylmetal derivative of L (e.g., alkylaluminum derivative, alkyltin derivative, alkylborane derivative, etc.).

[0352] (2) The intermediate of the compound represented by general formula (I), i.e., the compound (C-1) below, can also be produced by the following method, for example.

[0353] [ka]

[0354] (In the formula, each symbol has the same meaning as above.) Compound (C-1) is obtained by a coupling reaction between compound (17-1) and the boronic acid derivative (17-2). The reaction conditions are the same as those for step B-1 described above.

[0355] (3) The following steps are suitable for producing compounds in which L can be introduced by reaction with boronic acid (18-1) among the compounds (C-1) (for example, heteroaryls containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, with a ring structure of 3 to 10 atoms, olefins, and acetylenes, etc., which are unsubstituted or substituted and have 6 to 10 carbon atoms).

[0356] [ka]

[0357] (In the formula, each symbol has the same meaning as above.) Process C-4 Boronic acid (18-1) is obtained by the reaction of compound (16-1) with a boronic acid derivative (e.g., bispinacollate diborone, bisneopentylglycolate diborone, etc.). The reaction preferably proceeds in a suitable solvent in the presence of a palladium catalyst, phosphine ligand, and base, from 0°C to under heating, particularly from room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent listed in step B-1 can be used. Process C-5 Compound (C-1) is obtained by the reaction of boronic acid (18-1) with compound (18-2). The reaction preferably proceeds in a suitable solvent in the presence of a palladium catalyst, phosphine ligand, and base, from 0°C to heated, particularly from room temperature to the boiling point of the solvent. The palladium catalyst, phosphine ligand, base, and solvent listed in step B-1 can be used.

[0358] (4) Among the compounds represented by general formula (I), ring E is represented by the above general formula (Ea), G is a nitrogen atom and J is a nitrogen atom, R 9a The intermediate of a compound in which is a halogen atom, i.e., the compound (C-2) below, can be produced by, for example, the following manufacturing method.

[0359] [ka]

[0360] (In the formula, each symbol has the same meaning as above.) Process C-6 Compound (19-1) is obtained by reacting compound (B-11) and compound (16-4). The reaction conditions are the same as those for step C-2. Process C-7 Compound (19-1) is reacted with sulfuryl chloride, N-bromosuccinimide, etc., in acetic acid or a mixture of acetic acid and chloroform at room temperature to 50°C to obtain compound (C- 2) is obtained.

[0361] (Method D) (1) Among the compounds represented by general formula (I), a compound in which T is -CO-NH- and n is 2, i.e., the following compound (D-1), can be produced, for example, by the following manufacturing method.

[0362] [ka]

[0363] (In the formula, each symbol has the same meaning as above.) Process D-1 Compound (20-1) is a protecting group P of compound (C-1) C It is obtained by removing P C If it is a hydrogen atom, this step can be omitted. Protecting group P C The conditions for deprotection are, P C It is not particularly limited as long as it is used for deprotection, for example, P C If it is methyl, methods using a Lewis acid such as boron tribromide in a methylene chloride solvent or an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol-based solvent and water can be used. If it is ethyl, methods using an inorganic base such as sodium hydroxide in a mixed solvent of an alcohol-based solvent and water can be used. If it is t-butyl, methods using acids such as hydrochloric acid or trifluoroacetic acid can be used. Note that P C If the substance is benzyl, substituted benzyl, benzyloxymethyl, etc., a method using catalytic hydrogenation can be cited. Process D-2 Compound (D-1) is obtained by a condensation reaction between a carboxylic acid derivative (20-1) and an amine derivative (20-2). The reaction conditions are the same as those for step B-14 described above.

[0364] (2) Among the compounds represented by general formula (I), the compound in which T is -CO-NH- and n is 2, i.e., the compound (D-1) below, can be produced by the following method, for example.

[0365] [ka]

[0366] (In the formula, Z F (The symbols indicate chlorine and bromine atoms, and the other symbols have the same meaning as above.) Process D-3 This is a process for converting compound (20-1) to acid halide (21-1). The reaction proceeds in a suitable solvent, usually from 0°C to reflux temperature, and usually for 1 to 24 hours. Examples of halogenating agents include thionyl chloride, oxalyl chloride, and phenylphosphonyl dichloride. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, 1,2-dichloroethane, chloroform, pyridine, and toluene. Process D-4 Compound (D-1) is obtained by the reaction of an acid halide (21-1) with an amine derivative (20-2). The reaction proceeds using a base in a suitable solvent, usually from 0°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually 30 minutes to 12 hours. Examples of bases include triethylamine and pyridine. Examples of solvents include dichloromethane, dichloroethane, chloroform, N-methylpyrrolidone, pyridine, and toluene.

[0367] (Method E) (1) Among the compounds represented by general formula (I), the compound in which T is -CO-NH- and n is 2, i.e., the compound (D-1) below, can be produced by the following method, for example.

[0368] [ka]

[0369] (In the formula, each symbol has the same meaning as above.) Process E-1 Compound (22-2) is formed from amine (20-2) and HOC(O)-LZ A (In the formula, Z AIt is obtained by reaction with a carboxylic acid (22-1) represented by (which is synonymous with the above). The reaction conditions are the same as those for step B-14 described above. Process E-2 This step involves the reaction of compound (22-2) with a boronic acid or its ester derivative (18-1) to obtain compound (D-1). The reaction conditions are the same as those for step B-1.

[0370] (2) Among the compounds represented by general formula (I), the compound in which T is -CO-NH- and n is 2, i.e., the compound (D-1) below, can be produced by the following method, for example.

[0371] [ka]

[0372] (The symbols in the formula have the same meaning as above.) Process E-3 Compound (23-2) is obtained by the reaction of an amine derivative (20-2) and a carboxylic acid derivative (23-1). The reaction conditions are the same as those for step B-14 described above. 2 If the compound is an amine or otherwise has the potential for self-condensation, appropriate protection and deprotection steps can be included. Process E-4 The hydroxyl group of compound (16-2) is activated by the activating group OZ D This is a process of converting to [a specific substance]. The reaction conditions are the same as those for step C-1 described above. Process E-5 This step involves the reaction of compound (16-1), or compound (16-3) obtained in step E-4, with compound (23-2) to obtain compound (D-1). The reaction conditions are the same as those for step C-2 described above.

[0373] (3) Among the compounds represented by general formula (I), the compound in which T is -CO-NH- and n is 2, i.e., the compound (D-1) below, can be produced by the following method, for example.

[0374] [ka]

[0375] (The symbols in the formula have the same meaning as above.) In method E (2) described above, compound (24-1) is used instead of compound (23-1) to obtain the boronic acid derivative (24-2), and then compound (D-1) is obtained by reaction with iminochloride (A-4). The reaction conditions for step E-6 are the same as those for step B-14. The reaction conditions for step E-7 are the same as those for step B-1.

[0376] (Method F) (1) Among the compounds represented by general formula (I), the compound in which T is -CO-NH- and n is 2, i.e., the compound (D-1) below, can be produced by the following method, for example.

[0377] [ka]

[0378] (In the formula, P E (The symbol indicates a protecting group, and each other symbol has the same meaning as above.) P in the formula E The group is not particularly limited as long as it protects the thiol group and yields compound (25-5). Examples include the benzyl group. Process F-1 Compound (25-2) is obtained by the reaction of a carboxylic acid derivative (20-1) with an amine derivative (25-1). The reaction conditions are the same as those for step B-14 described above. Process F-2 Compound (25-2) and P E This step involves the reaction with SH(25-3) to obtain compound (25-4). The reaction conditions are the same as those for step C-2 described above. Process F-3 Compound (25-5) is obtained by reacting compound (25-4) with N-chlorosuccinimide or the like in a mixture of acetonitrile and hydrochloric acid, or in acetic acid, at a temperature of 0°C to 50°C. Process F-4 Compound (D-1) is obtained by reacting a sulfonyl chloride derivative (25-5) with an amine derivative (25-6). The reaction proceeds using a base in a suitable solvent, usually at 0°C to the reflux temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually between 0.5 and 24 hours. Examples of bases include triethylamine and pyridine. Examples of solvents include tetrahydrofuran, dichloromethane, and acetonitrile.

[0379] (2) Among the compounds shown in (20-2) above, the fused ring portion is 3-cyano-1H- The compound that is ndol, namely the compound (F-1) below, can be produced, for example, by the following manufacturing method.

[0380] [ka]

[0381] (In the formula, P F (The symbol indicates a protecting group for an amino group, and the other symbols have the same meaning as above.) P in the formula F The amino group is not particularly limited as long as it protects the amino group and yields compound (26-6). Examples include the t-butyloxycarbonyl group and the benzyloxycarbonyl group. Process F-5 Compound (26-3) is obtained by the reaction of nitro compound (26-1) with vinylmagnesium bromide (26-2). The reaction proceeds in a suitable solvent, usually from -78°C to room temperature. The reaction time varies depending on the starting materials, solvent, and reaction temperature, but is usually from 0.5 hours to 24 hours. A suitable solvent is, for example, tetrahydrofuran. Process F-6 Compound (26-4) can be obtained, for example, by formylation of the indole derivative (26-3), followed by oxime formation and dehydration. The formylation reaction proceeds using a halogenating agent and DMF, usually from room temperature to reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature, but is usually from 1 to 24 hours. Examples of halogenating agents include phosphoryl chloride and phenylphosphonyl dichloride. Examples of solvents include DMF or a dichlorobenzene-DMF mixed solution. Compound (26-4) can also be obtained by adding hydroxylamine hydrochloride to the above reaction solution and heating it. The reaction usually proceeds from 40°C to reflux temperature. The reaction time varies depending on the raw materials, solvent, and reaction temperature, but is usually from 0.5 to 24 hours. Process F-7 Compound (26-5) is obtained by a coupling reaction between compound (26-4) and benzophenone imine, followed by a deprotection reaction. The reaction conditions for the coupling reaction are the same as those for step C-2. For the deprotection reaction, an acid such as hydrochloric acid or a hydroxylamine is used. The reaction usually proceeds from room temperature to the reflux temperature of the solvent. The reaction time varies depending on the raw materials, solvent, and reaction temperature used, but is usually from 1 to 24 hours. Examples of solvents include methanol, tetrahydrofuran, 1,4-dioxane, or mixed solutions thereof. Process F-8 Compound (26-7) is obtained by reacting a sulfonyl chloride derivative (26-6) with an amine derivative (26-5). The reaction conditions for step F-8 are the same as those for step F-4. Process F-9 Compound (F-1) is the protecting group P of compound (26-7). F It is obtained by removing P. The conditions for deprotection are, F It is not particularly limited as long as it is used for deprotection, for example, P FIf the group is a t-butyloxycarbonyl group, it can be deprotected with an acid. Examples of suitable acids include inorganic acids such as hydrochloric acid and trifluoroacetic acid. Reaction conditions include using an alcoholic solvent such as ethanol, an ether-based solvent such as tetrahydrofuran, water, or a mixture thereof, under ice cooling at ~80°C for approximately 10 minutes to 12 hours. F If the group is a benzyloxycarbonyl group, deprotection can be achieved by reduction via catalytic hydrogenation. Examples of catalysts include palladium carbon. The reaction temperature is typically room temperature to the reflux temperature of the solvent, the hydrogen pressure is 1 to 20 atmospheres, and the reaction time varies depending on the raw materials, solvent, and reaction temperature, but is usually between 1 and 48 hours.

[0382] The compound represented by general formula (I) produced by the method described above can be purified to any desired purity by conventional purification methods, such as concentration, extraction, chromatography, reprecipitation, and recrystallization. Furthermore, it can be treated with an acid or base in a suitable solvent (water, alcohol, ether, etc.) as needed to obtain a pharmaceutically acceptable salt. In addition, the obtained compound of the present invention or its pharmaceutically acceptable salt can be treated with water, an aqueous solvent, or other solvent to obtain a hydrate or solvate.

[0383] The compounds of the present invention or pharmaceutically acceptable salts thereof include racemic compounds, stereoisomers, and mixtures thereof, and include isotopically labeled and radioactively labeled compounds. Such isomers can be isolated by standard separation techniques, including fractional crystallization and chiral column chromatography. The compounds of the present invention also have an asymmetric carbon atom. Therefore, they include enantiomers or diastereomers. Diastereomer mixtures can be separated into their individual diastereomers based on their physical / chemical differences, by methods known in the prior art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by chiral column chromatography or by reacting an enantiomer compound with a suitable optically active compound to convert it into a diastereomer mixture, separating each diastereomer, and then converting the individual diastereomers to their corresponding enantiomers. The compounds of the present invention may be any isomers, including diastereomers, enantiomers, and mixtures thereof.

[0384] The compound of the present invention or its pharmaceutically acceptable salt has cytotoxic effects on cancer cells. Furthermore, it also has the effect of inducing the degradation of BET protein in cancer cells and inhibiting the binding of BET protein to acetylated histones. Therefore, the compound of the present invention or its pharmaceutically acceptable salt can be used as an anticancer agent, and can also be used as a BET protein degradation inducer or BET protein inhibitor. In addition, according to the present invention, it is possible to provide a method for treating cancer, a method for inducing the degradation of BET protein, and a method for inhibiting BET protein using the compound of the present invention or its pharmaceutically acceptable salt.

[0385] Furthermore, the compound of the present invention or its pharmaceutically acceptable salt also has the effect of inducing the degradation of BRD4 protein in cancer cells and inhibiting the binding of BRD4 protein to acetylated histones. Therefore, the compound of the present invention or its pharmaceutically acceptable salt can be used as a BRD4 protein degradation inducer or a BRD4 protein inhibitor. In addition, according to the present invention, it is also possible to provide a method for treating cancer, a method for inducing the degradation of BRD4 protein, and a method for inhibiting BRD4 protein using the compound of the present invention or its pharmaceutically acceptable salt.

[0386] In this invention, cancer refers to any type of cancer, but specific examples include oral cancer, pharyngeal cancer, laryngeal cancer, thyroid cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, large intestine cancer, anal cancer, liver cancer, biliary tract cancer, pancreatic cancer, gastrointestinal stromal tumors, lung cancer, skin cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular tumors, bladder cancer, kidney cancer, urothelial carcinoma, brain tumors, bone and soft tissue tumors, leukemia, malignant lymphoma, multiple myeloma, and sarcomas (e.g., Ewing's sarcoma, rhabdomyosarcoma, bone and soft tissue sarcoma).

[0387] In the medical field, colorectal cancer is sometimes called colon cancer or rectal cancer, liver cancer is called hepatocellular carcinoma, biliary tract cancer is called bile duct cancer or gallbladder cancer, pancreatic cancer is called pancreatic ductal carcinoma or pancreatic endocrine tumor, lung cancer is called non-small cell lung cancer, small cell lung cancer, large cell lung cancer, malignant pleural mesothelioma or thymic tumor, skin cancer is called cutaneous malignant tumor or cutaneous lymphoma, uterine cancer is called cervical cancer, uterine body cancer or uterine sarcoma, kidney cancer is called renal cell carcinoma, urothelial carcinoma is called renal pelvis cancer or ureteral cancer, and brain tumors are sometimes called gliomas. Furthermore, breast cancer has subtypes such as triple-negative breast cancer, HER2-positive breast cancer, luminal A-type breast cancer, and luminal B-type breast cancer; prostate cancer has subtypes such as hormone-dependent prostate cancer, hormone-independent prostate cancer, and castration-resistant prostate cancer; and leukemia has subtypes such as acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL). Malignant lymphoma has subtypes such as myelodysplastic syndrome (MDS), follicular lymphoma (FL), MALT lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (LPL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL, NOS), Burkitt lymphoma (BL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia / lymphoma (ATL), extranodal NK / T-cell lymphoma, nasal type (ENKL), and Hodgkin lymphoma (HL).

[0388] In one embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, adult T-cell leukemia / lymphoma, Burkitt lymphoma, prostate cancer, ovarian cancer, bladder cancer, breast cancer, cervical cancer, uterine sarcoma, gastric cancer, lung cancer, colorectal cancer, glioma, pancreatic cancer, liver cancer, cholangiocarcinoma, renal cell carcinoma, and fibrosarcoma. In another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, multiple myeloma, Burkitt lymphoma, glioma, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, non-small cell lung cancer, breast cancer, ovarian cancer, and uterine sarcoma. In yet another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. In yet another embodiment, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, ovarian cancer, and breast cancer.

[0389] In this specification, the term "anticancer agent" is a concept that includes anticancer agents, antitumor agents, etc., and has the effect of damaging, killing, or weakening cancer cells or tumor cells for the purpose of treating cancer, thereby reducing or eliminating abnormally proliferating cell masses, or preventing their growth. Furthermore, "treatment" means the act of administering the compound of the present invention, its pharmaceutically acceptable salt, or a pharmaceutical composition containing these to an individual who has already developed a disease, disorder, or symptoms. Accordingly, the act of administering a compound to an individual who has already developed a disease, disorder, or symptoms in order to prevent the worsening of symptoms or to prevent recurrence is one form of treatment.

[0390] When the compound of the present invention is used as a pharmaceutical, it can be administered orally or parenterally as a pharmaceutical composition obtained by mixing the compound with pharmaceutically acceptable additives (excipients, binders, disintegrants, flavoring agents, odoring agents, emulsifiers, diluents, solubilizers, etc.). The pharmaceutical composition can be formulated according to conventional methods.

[0391] The target population for administration of the compound or pharmaceutical composition of the present invention is not particularly limited, but mammals are preferred. Examples of mammals include primates (e.g., humans, monkeys, chimpanzees), rodents (e.g., mice, rats, guinea pigs), pets (e.g., dogs, cats, rabbits), working animals, or livestock (e.g., cattle, horses, pigs, sheep, goats), but humans are preferred.

[0392] In this specification, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intravenous drip infusion, or local administration (such as intra-articular administration, transdermal administration, transocular administration, transpulmonary / bronchial administration, transnasal administration, or transrectal administration).

[0393] The dosage of the compound of the present invention is determined by considering age, weight, general health status, sex, diet, administration time, method of administration, excretion rate, and the severity of the patient's current medical condition, as well as other factors. The daily dosage of the compound of the present invention varies depending on the patient's condition, weight, type of compound, and route of administration, but for example, parenterally it is administered subcutaneously, intravenously, intramuscularly, intra-articularly, percutaneously, transocularly, transpulmonaryly / bronchially, transnasally, or rectally at a dose of approximately 0.001 to 100 mg / person / day, and orally at a dose of approximately 0.01 to 1000 mg / person / day. [Examples]

[0394] The present invention will be described in detail below with reference to examples, embodiments, and test examples, but the present invention is not limited in any way by these.

[0395] Reference example 1 (1-1) Methyl [(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Reference compound 1)

[0396] [ka]

[0397] (6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (300 g) was added dropwise to a methanol (1.5 L) suspension over ice cooling with thionyl chloride (320 g) over 1 hour (10-25°C), and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure, chloroform (1.5 L) and water (1 L) were added, and the mixture was separated and further extracted with chloroform (500 mL). The organic layer was washed with saturated sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure (azeotropic twice with methanol). The residue was washed with methanol / water (300 mL / 300 mL) to obtain the title compound (250 g). MS(ESI)m / z:415.2[M+H] +

[0398] Reference example 2 (2-1) 3-(4-bromophenyl)-3-oxopropannitrile (Reference compound 2-1)

[0399] [ka]

[0400] At room temperature, acetonitrile (12.3 g) was added to a suspension of sodium methoxide (12.4 g) in dimethyl sulfoxide (23 mL), and the mixture was stirred at room temperature for 2 hours. Then, a solution of ethyl 4-bromobenzoate (22.9 g) in dimethyl sulfoxide (23 mL) was slowly added, and the mixture was stirred at 45°C for 3 hours. The reaction solution was cooled with ice, water and concentrated hydrochloric acid were added, and the mixture was stirred for 0.5 hours. The precipitate was then filtered off. The resulting residue was dried to obtain the title compound (22.4 g) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ4.75(brs,2H),7.87-7.70(m,4H)

[0401] (2-2) (2-amino-4,5-dimethylthiophen-3-yl)(4-bromophenyl)methanone (Reference compound 2-2)

[0402] [ka]

[0403] A mixture of reference compound 2-1 (25.0 g), ethyl methyl ketone (8.0 g), sulfur (3.6 g), morpholine (9.7 mL), and ethanol (325 mL) was stirred at 70°C for 7 hours. After removing the solvent by distillation, ethyl acetate was added. The organic layer was washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained solid, and after stirring at room temperature for 2 hours, the precipitate was filtered off to obtain the title compound (13.5 g) as a yellow solid. MS(ESI)m / z:310.2,312.1[M+H] +

[0404] (2-3)(3S)-5-(4-bromophenyl)-3,6,7-trimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepine-2-one (Reference compound 2-3)

[0405] [ka]

[0406] Under ice cooling, (2S)-2-(t-butoxycarbonylamino)propanoic acid (27.6 g) and pyridine (200 mL) were added to reference compound 2-2 (43.0 g), and then phenylphosphonyl dichloride (29.7 g) was slowly added dropwise, and the mixture was stirred under ice cooling for 1 hour. After removing the solvent by distillation, ethyl acetate was added, and the organic layer was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (53 mL) was added to the obtained residue in a dichloromethane (70 mL) solution, and the mixture was stirred at room temperature for 2 hours, then trifluoroacetic acid (53 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and azeotropically analyzed using toluene. Saturated sodium bicarbonate solution was added to the obtained mixture, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Acetic acid (12 mL) was added to the 2-propanol (200 mL) suspension of the obtained residue, and the mixture was stirred at 90°C for 1 hour. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction mixture and extracted. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (43 mL) was added to the obtained residue, and the mixture was stirred at 45°C for 1 hour, after which the insoluble matter was filtered off. The resulting solid was dried under reduced pressure to obtain the title compound (25.7 g) as a yellow solid. MS(ESI)m / z:363.2,365.2[M+H] +

[0407] (2-4)(6S)-4-(4-bromophenyl)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Reference compound 2)

[0408] [ka]

[0409] Under ice cooling, sodium hydride (60%, 1.1g) was added to a solution of reference compound 2-3 (9.6g) in tetrahydrofuran (65mL) and stirred for 0.5 hours. Then, diethylphosphonyl chloride (5.5g) was added and stirred at room temperature for 0.25 hours. Acetohydrazide (2.9g) and n-butanol (10mL) were added and stirred at 70°C for 0.5 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate) to obtain the title compound (8.9g) as a yellow powder. MS(ESI)m / z:401.1,403.1[M+H] +

[0410] Reference example 3 (3-1) Methyl {(6S)-2,3,9-trimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Reference compound 3)

[0411] [ka]

[0412] Under an argon atmosphere, Reference Compound 1 (5.00 g), bis(pinacolate)diborone (4.59 g), potassium acetate (2.37 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were heated under reflux in tetrahydrofuran solvent for 25 hours. Further addition of dichlorobis(tricyclohexylphosphine)palladium (445 mg) and bis(pinacolate)diborone (1.53 g) was added and heated under reflux for 7 hours. Then, bis(pinacolate)diborone (1.53 g), potassium acetate (1.18 g), and dichlorobis(tricyclohexylphosphine)palladium (445 mg) were added and heated under reflux for 16 hours. The mixture was cooled to room temperature and filtered through Celite using ethyl acetate. The filtrate was washed twice with saturated brine, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100:0 to 97:3), followed by further purification by silica gel column chromatography (ethyl acetate / methanol = 100:0 to 95:5) to obtain the title compound (5.27 g) as a pale yellow solid. MS(ESI) m / z: 507.2[M+H] +

[0413] Reference example 4 (4-1) t-butyl 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Reference compound 4-1)

[0414] [ka]

[0415] A mixture of Reference Example Compound 1 (5.00 g), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.03 g), potassium fluoride (2.10 g), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (hereinafter referred to as S-phos, 495 mg), palladium acetate (271 mg), tetrahydrofuran (40.2 mL), and water (0.78 mL) was stirred under reflux for 40 hours. Then, (4-t-butoxycarbonylphenyl)boronic acid (803 mg), S-phos (247 mg), palladium acetate (135 mg), and water (0.78 mL) were added and the mixture was stirred for another 20 hours. Ethyl acetate was added to the reaction mixture, and insoluble matter was filtered off using diatomaceous earth. The filtrate was then concentrated under reduced pressure. Chloroform and water were added to the residue, and the organic layer was extracted. The aqueous layer was then re-extracted with chloroform. The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5). Further purification was performed by silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (6.55g) as a crude yellow solid. MS(ESI)m / z:557.3[M+H] +

[0416] (4-2)4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylic acid (Example compound 4)

[0417] [ka]

[0418] Reference compound 4-1 (7.05 g) was dissolved in chloroform (8.0 mL), and trifluoroacetic acid (8.0 mL) was added at room temperature. The mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and toluene azeotrope was performed twice. The mixture was dissolved in ethyl acetate, cooled to 0°C, and saturated sodium bicarbonate solution was gradually added to adjust the pH to 8. The organic layer was separated and washed with ethyl acetate. 1N hydrochloric acid was slowly added to the aqueous layer to adjust the pH to 5, and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure to obtain a pale yellow solid (6.29 g). MS(ESI) m / z: 501.2[M+H] +

[0419] Reference example 5 (5-1) N-(3-cyano-4-methyl-1H-indole-7-yl)-4-formylbenzene-1-sulfonamide (Reference compound 5-1)

[0420] [ka]

[0421] In a solution of reference compound 9 (100 mg) and 4-formylbenzenesulfonyl chloride (132 mg) in tetrahydrofuran (6.0 mL), pyridine (0.29 mL) was added at room temperature and the mixture was stirred for 16 hours at the same temperature. 4-formylbenzenesulfonyl chloride (48 mg) was added and the mixture was stirred for 1 hour at room temperature. 1N hydrochloric acid was added to the reaction mixture to make it acidic, and then it was extracted twice with ethyl acetate. The organic layer was dried and filtered over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0~40:60). Chloroform was added to the purified product, and after solidification, the title compound (126 mg) was obtained as a yellow powder by vacuum concentration. MS(ESI)m / z:340.1[M+H] +

[0422] (5-2) 4-(azidomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Reference compound 5-2)

[0423] [ka]

[0424] To a methanol (21.0 mL) solution of reference compound 5-1 (730 mg), sodium borohydride (163 mg) was added at room temperature and the mixture was stirred at the same temperature for 20 minutes. 1N hydrochloric acid-water-saturated brine and ethyl acetate-acetone were added to the reaction mixture and separated. The aqueous layer was extracted once with ethyl acetate, and the combined organic layers were dried and filtered over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (30.0 mL), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.49 mL) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature and the mixture was stirred at the same temperature for 15 hours. 1,8-Diazabicyclo[5.4.0]-7-Undecene (0.486 mL) and 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate (736 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. 1N hydrochloric acid was added to the reaction mixture, and it was extracted twice with ethyl acetate. The organic layer was dried and filtered over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0~60:40). Chloroform was added to the purified product, and after solidification, the product was concentrated under reduced pressure to obtain the title compound (355 mg) as a pale yellow powder. MS(ESI)m / z:365.3[MH] -

[0425] (5-3) 4-(aminomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Reference compound 5)

[0426] [ka]

[0427] A mixture of reference compound 5-2 (350 mg) and triphenylphosphine (326 mg) was mixed with tetrahydrofuran (10.0 mL) and water (1.0 mL), and stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added to the resulting residue, and the precipitate was filtered to obtain the title compound (300 mg) as a white powder. MS(ESI)m / z:341.1[M+H] +

[0428] Reference example 6 (6-1)4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]benzoic acid (Reference compound 6)

[0429] [ka]

[0430] A mixture of Reference Example Compound 9 (1.00 g) and tetrahydrofuran (30.0 mL) was mixed with 4-chlorosulfonylbenzoic acid (1.42 g) under ice cooling and stirred at room temperature for 24 hours. 1N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitate was filtered off to obtain the title compound (1.81 g) as a brown solid. MS(ESI)m / z: 354.1[MH] -

[0431] Reference example 7 (7-1)7-bromo-4-methyl-1H-indole (Reference compound 7)

[0432] [ka]

[0433] To a tetrahydrofuran solution (35.0 mL) of 1-bromo-4-methyl-2-nitrobenzene (1.08 g), a 1M vinylmagnesium bromide / tetrahydrofuran solution (15.0 mL) was added at -40°C. After stirring at the same temperature for 40 minutes, saturated ammonium chloride aqueous solution and water were added to the reaction mixture and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 98:2~95:5) to obtain the title compound (600 mg) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ ppm 2.52(3H,d,J=0.77Hz),6.63(1H,dd,J=3.28,2.25Hz),6.80(1H,dq,J=7.71,0.81Hz),7.22-7.27(2H,m),8.32(1H,brs)

[0434] Reference example 8 (8-1)7-bromo-4-methyl-1H-indole-3-carbonitride (Reference compound 8)

[0435] [ka]

[0436] To a 1.35 mL solution of Reference Example Compound 7 (284 mg) in N,N-dimethylformamide, phenylphosphonyl dichloride (0.23 mL) was added at room temperature. After stirring at room temperature for 0.5 hours, phenylphosphonyl dichloride (0.04 mL) was added, and the mixture was stirred for a further 0.5 hours at the same temperature. Hydroxylamine hydrochloride (188 mg) was added to the reaction mixture at room temperature, and the mixture was heated and stirred at 60°C for 1 hour and at 100°C for 2 hours. The reaction solution was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate solution and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (220 mg) as a light brown solid. 1H NMR(400MHz,CDCl3)δ ppm 2.75(3H,d,J=0.6Hz),6.92(1H,dq,J=7.6,1.8Hz),7.36(1H,d,J=7.7Hz),7.78(1H,d,J=2.8Hz),8.73(1H,brs)

[0437] Reference example 9 (9-1)7-amino-4-methyl-1H-indole-3-carbonitride (Reference compound 9)

[0438] [ka]

[0439] A mixture of Reference Compound 8 (215 mg), benzophenone imine (240 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 22 mg), and tetrahydrofuran (2.3 mL) was mixed with 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.5 mL) at room temperature and stirred at 120 °C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (2.3 mL)-methanol (2.3 mL), hydroxylamine hydrochloride (159 mg) and sodium acetate (225 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (139 mg) as a light brown solid. MS(ESI)m / z:172.1[M+H] +

[0440] Reference example 10 (10-1) Methyl [(6S)-4-(4'-{[(4-bromophenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Reference compound 10-1)

[0441] [ka]

[0442] In a solution of reference compound 4 (500 mg) and 4-bromobenzylamine (223 mg) in N,N-dimethylformamide (5.0 mL), N,N-diisopropylethylamine (0.52 mL) and HATU (456 mg) were added at room temperature and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (643 mg) as a pale yellow powder. MS(ESI)m / z:668.3,670.3[M+H] +

[0443] (10-2) Methyl {(6S)-4-[4'-({[4-(benzylsulfanyl)phenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Reference compound 10-2)

[0444] [ka]

[0445] A mixture of reference compound 10-1 (635 mg), benzyl mercaptan (0.14 mL), N,N-diisopropylethylamine (0.50 mL), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (Xantphos, 110 mg), tris(dibenzylideneacetone)dipalladium (87 mg), toluene (9.0 mL), and tetrahydrofuran (3.0 mL) was stirred at 150°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction solution was directly purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (613 mg) as a pale yellow powder. MS(ESI)m / z:712.4[M+H] +

[0446] (10-3) Methyl {(6S)-4-[4'-({[4-(chlorosulfonyl)phenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Reference compound 10)

[0447] [ka]

[0448] In a solution of compound 10-2 (594 mg) in acetonitrile (12.0 mL) and 2N hydrochloric acid (2.4 mL), N-chlorosuccinimide (390 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (23 mg) was added to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hours. Saturated brine and water (1:1) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (570 mg) as a pale yellow powder. MS(ESI)m / z:670.4[M-Cl+H2O] + ; 1H NMR(400MHz,CDCl3) δ ppm 1.75(3H,d,J=0.64Hz),2.41-2.46(3H,m),2.70(3H,s),3.66(2H,dd,J=7.06,3.72Hz),3.79(3H,s),4.44(1H,d,J=5.65Hz),4.67(1H, dd,J=7.77,6.36Hz),4.80(2H,d,J=6.04Hz),7.55-7.63(6H,m),7.68(2H,m,J=8.61Hz),7.90(2H,m,J=8.61Hz),8.02(2H,d,J=7.74Hz)

[0449] Reference example 11 (11-1) t-butyl (2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl) carbamate (Reference compound 11-1)

[0450] [ka]

[0451] A mixed solution of reference compound 9 (120 mg), t-butyl N-2-[4-(chlorosulfonyl)phenyl]ethyl carbamate (250 mg), pyridine (0.28 mL), and tetrahydrofuran (5.0 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, and then dried and filtered over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resulting residue was suspended and washed with hexane, and then filtered to obtain the title compound (301 mg) as a pale yellow solid. MS(ESI)m / z:455.4[M+H] +

[0452] (11-2) 4-(2-aminoethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Reference compound 11)

[0453] [ka]

[0454] Compound 11-1 (301 mg) was added to 3.0 mL of 4 M hydrogen chloride / 1,4-dioxane solution at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and then filtered to obtain the title compound (260 mg) as a milky white solid. MS(ESI)m / z:355.1[M+H] +

[0455] Reference example 12 (12-1) t-butyl 3-fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Reference compound 12-1)

[0456] [ka]

[0457] Reference compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), and t-butyl 4-bromo-2-fluorobenzoate (196 mg), tetrakis(triphenylphosphine)palladium (0) (69 mg), potassium phosphate (377 mg), and water (0.038 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, and insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~98:2, pre-column: NH silica gel) to obtain the title compound (346 mg) as a crude white powder. MS(ESI)m / z:575.4[M+H] +

[0458] (12-2)3-fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference compound 12)

[0459] [ka]

[0460] Reference compound 12-1 (240 mg) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and extracted twice with saturated sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was gradually added under ice cooling to adjust the pH to 4. The combined organic layers were extracted twice with chloroform, washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (205 mg) as a white powder. MS(ESI)m / z: 519.1[M+H] +

[0461] Reference example 13 (13-1)3-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference compound 13)

[0462] [ka]

[0463] Reference compound 3 (117 mg) was dissolved in tetrahydrofuran (1.0 mL), and 4-bromo-2-chlorobenzoic acid (48 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 10 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (16 mg), cesium fluoride (93 mg), and water (0.25 mL) were added. The mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was gradually added under ice cooling to adjust the pH to 1. The aqueous layers were extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying and filtering with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain the title compound (73 mg) as a white powder. MS(ESI)m / z:535.1,537.1[M+H] +

[0464] Reference example 14 (14-1) 4-bromo-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Reference compound 14)

[0465] [ka]

[0466] To a tetrahydrofuran solution (12.0 mL) of reference compound 9 (622 mg) and pyridine (2.92 mL), 4-bromobenzenesulfonyl chloride (929 mg) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed once with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was suspended and washed with chloroform, and then filtered to obtain the title compound (1061 mg) as a beige powder. MS(ESI)m / z:390.2,392.1[M+H] +

[0467] Reference example 15 (15-1)7-amino-4-bromo-1H-indole-3-carbonitride (Reference compound 15)

[0468] [ka]

[0469] N,N-dimethylformamide (11.0 mL) was mixed with phenylphosphonyl dichloride (1.27 mL) and stirred at 70°C for 10 minutes. Then, N-(4-bromo-1H-indole-7-yl)-2,2,2-trifluoroacetamide (929 mg) and N,N-dimethylformamide (11.0 mL) were added and stirred at 70°C for 1 hour. Next, hydroxylamine hydrochloride (2.42 g) was added and stirred at 100°C for 2 hours. Furthermore, ethylenediamine (2.02 mL) and methanol (22.0 mL) were added and stirred at 70°C for 1 hour. After cooling to room temperature, methanol was removed by distillation under reduced pressure, and ethyl acetate, saturated sodium bicarbonate solution, and saturated saline solution were added to the resulting residue and separated. The organic layer was washed twice with a mixture of saturated sodium bicarbonate solution and saturated saline solution, once with water, and once with saturated saline solution. After drying and filtering over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was suspended and washed with ethyl acetate, filtered, and dried under reduced pressure to obtain the title compound (260 mg) as a brown powder. The filtrate was then desolvented under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50~75:25) to obtain the target compound (104 mg) as a brown solid. MS(ESI) m / z: 236.0, 237.9 [M+H] +

[0470] Reference example 16 (16-1) 7-bromo-4-ethyl-1H-indole-3-carbonitride (Reference compound 16-1)

[0471] [ka]

[0472] To a 17.4 mL solution of 7-bromo-4-ethyl-1H-indole (3.90 g) in N,N-dimethylformamide, phenylphosphonyl dichloride (3.64 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 70°C for 40 minutes. Hydroxylamine hydrochloride (2.42 g) was added, and the mixture was stirred at 70°C for 30 minutes and at 80°C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, cooled on ice, and saturated sodium bicarbonate solution was added while stirring. The mixture was extracted twice with ethyl acetate, the extracts were combined, washed twice with a mixture of saturated saline and saturated sodium bicarbonate solution, and once with saturated saline, and then dried and filtered over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10~70:30), and the residue was concentrated under reduced pressure by adding toluene, repeating this process twice. The title compound (3.12 g) was obtained as a pale yellow solid. MS(ESI)m / z: 246.9,248.9[MH] -

[0473] (16-2) 7-amino-4-ethyl-1H-indole-3-carbonitride (Reference compound 16)

[0474] [ka]

[0475] A mixture of reference compound 16-1 (2.12 g), benzophenone imine (2.16 g), and [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 202 mg) was mixed with 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (23.0 mL) at room temperature, and the mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (11.0 mL)-methanol (11.0 mL), and hydroxylamine hydrochloride (1.48 g) and sodium acetate (2.09 g) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was combined with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed once with a mixture of saturated brine and water, and once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~98:2) to obtain the title compound (954 mg) as a light brown solid. MS(ESI)m / z:186.1[M+H] +

[0476] Reference example 17 (17-1) t-butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (Reference compound 17-1)

[0477] [ka]

[0478] Di-t-butyl carbonate (3.60 g) was added to a 45.0 mL dichloromethane solution (3.00 g) of (R)-1-(4-bromophenyl)ethaneamine and triethylamine (2.50 mL) at room temperature, and the mixture was stirred at room temperature for 14 hours. 1N hydrochloric acid was added to the reaction mixture, and the solution was separated. The aqueous layer was extracted once with chloroform, and the combined organic layers were dried and filtered over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. The resulting residue was washed with hexane and filtered to obtain the title compound (4.36 g) as a white solid. MS(ESI)m / z: 300.2,302.1[M+H] +

[0479] (17-2) t-butyl {(1R)-1-[4-(benzylsulfanyl)phenyl]ethyl}carbamate (Reference compound 17-2)

[0480] [ka]

[0481] A mixture of reference compound 17-1 (4.34 g), benzyl mercaptan (2.04 mL), N,N-diisopropylethylamine (3.75 mL), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (Xantphos, 1.67 g), tris(dibenzylideneacetone)dipalladium (1.32 g), and toluene (10.0 mL) was stirred at 150°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. Ethyl acetate was added to the reaction mixture, and insoluble matter was filtered off using diatomaceous earth. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10~80:20) to obtain the title compound (4.91 g) as a pale yellow solid. MS(ESI) m / z: 344.3 [M+H] +

[0482] (17-3) t-butyl {(1R)-1-[4-(chlorosulfonyl)phenyl]ethyl}carbamate (Reference compound 17-3)

[0483] [ka]

[0484] To a solution of reference compound 17-2 (2.72 g) in acetonitrile (50.0 mL) and 2N hydrochloric acid (10.0 mL), N-chlorosuccinimide (4.30 g) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and it was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10~75:25) to obtain the title compound (2.21 g) as a white solid. 1 H NMR(400MHz,CDCl3) δ ppm 1.32-1.51(12H,m),4.87(2H,brs),7.48-7.60(2H,m),7.93-8.06(2H,m)

[0485] (17-4) t-butyl [(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference compound 17-4)

[0486] [ka]

[0487] To a solution of Reference Compound 17-3 (2.20 g) in tetrahydrofuran (66.0 mL), Reference Compound 9 (1.18 g) and pyridine (2.77 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, and then dried and filtered over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended and washed with chloroform, and filtered to obtain the title compound (1.67 g) as a light brown solid. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (0.84 g) as a light brown solid. MS(ESI)m / z:455.3[M+H] +

[0488] (17-5) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Reference compound 17)

[0489] [ka]

[0490] Compound 17-4 (2.47 g) was added to a 4M hydrogen chloride / 1,4-dioxane solution (25.0 mL) at room temperature. After stirring at the same temperature for 3 hours, the reaction mixture was diluted with diethyl ether, the solid was suspended and washed, and then filtered to obtain the title compound (2.27 g) as a milky white solid. MS(ESI)m / z:355.2[M+H] +

[0491] Reference example 18 (18-1) t-butyl 2-fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Reference compound 18-1)

[0492] [ka]

[0493] Reference compound 3 (300 mg) was dissolved in tetrahydrofuran (3.0 mL), and t-butyl 4-bromo-3-fluorobenzoate (180 mg), tetrakis(triphenylphosphine)palladium (0) (69 mg), potassium phosphate (378 mg), and water (0.039 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (300 mg) as a white powder. MS(ESI) m / z: 575.3 [M+H] +

[0494] (18-2)2-Fluoro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference compound 18)

[0495] [ka]

[0496] Reference compound 18-1 (290 mg) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and extracted twice with saturated sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was gradually added under ice cooling to adjust the pH to 4. The combined organic layers were extracted twice with chloroform, washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (246 mg) as a white powder. MS(ESI) m / z: 519.3[M+H] +

[0497] Reference example 19 (19-1) 2-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylic acid (Reference compound 19)

[0498] [ka]

[0499] Reference compound 3 (364 mg) was dissolved in tetrahydrofuran (3.2 mL), and 4-bromo-3-chlorobenzoic acid (150 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 30 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (50 mg), cesium fluoride (290 mg), and water (0.80 mL) were added. The mixture was stirred at 120 °C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was gradually added under ice cooling to adjust the pH to 1. The aqueous layers were extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying and filtering with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain the title compound (247 mg) as a pale yellow powder. MS(ESI)m / z:535.3,537.3[M+H] +

[0500] Reference example 20 (20-1)4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylic acid (Reference compound 20)

[0501] [ka]

[0502] Reference compound 3 (231 mg) was dissolved in tetrahydrofuran (2.0 mL), and 4-bromo-2-methylbenzoic acid (87 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 19 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (32 mg), cesium fluoride (185 mg), and water (0.50 mL) were added. The mixture was stirred at 120 °C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate and extracted twice with saturated sodium bicarbonate solution. The aqueous layers were combined, and 2N hydrochloric acid was gradually added under ice cooling to adjust the pH to 1. The aqueous layers were extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain the title compound (229 mg) as a crude white powder. MS(ESI)m / z:515.3[M+H] +

[0503] Reference example 21 (21-1) t-butyl ({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamate (Reference compound 21-1)

[0504] [ka]

[0505] To a solution of tetrahydrofuran (9.4 mL) of reference compound 16 (347 mg), t-butyl N-[(4-chlorosulfonylphenyl)methyl]carbamate (630 mg) and pyridine (0.76 mL) were added at room temperature and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, and after drying and filtration over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was washed with diethyl ether-hexane (1:1) and then filtered to obtain the title compound (730 mg) as a beige solid. MS(ESI)m / z:453.3[MH] -

[0506] (21-2) 4-(aminomethyl)-N-(3-cyano-4-ethyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Reference compound 21)

[0507] [ka]

[0508] Reference compound 21-1 (720 mg) was added to a 4M hydrogen chloride / 1,4-dioxane solution (7.2 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, the solid was suspended and washed, and then filtered to obtain the title compound (653 mg) as a beige solid. MS(ESI)m / z:355.0[M+H] +

[0509] Reference example 22 (22-1) t-butyl [(1R)-1-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamate (Reference compound 22-1)

[0510] [ka]

[0511] To a solution of Reference Compound 16 (300 mg) in tetrahydrofuran (8.0 mL), Reference Compound 17-3 (570 mg) and pyridine (0.65 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, and then dried and filtered over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resulting residue was suspended and washed with hexane-chloroform (15:1), and then filtered to obtain the title compound (710 mg) as a light brown solid. MS(ESI)m / z:467.3[MH] -

[0512] (22-2) 4-[(1R)-1-aminoethyl]-N-(3-cyano-4-ethyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Reference compound 22)

[0513] [ka]

[0514] 701 mg of reference compound 22-1 was added to 7.0 mL of a 4 M hydrogen chloride / 1,4-dioxane solution at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, and the solid was collected by filtration to obtain the title compound (653 mg) as a beige solid. MS(ESI) m / z: 369.1 [M+H] +

[0515] Reference example 23 (23-1) t-butyl (2-{4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl) carbamate (Reference compound 23-1)

[0516] [ka]

[0517] To a solution of 300 mg of compound 16 in 8.0 mL of tetrahydrofuran, 570 mg of t-butyl N-2-[4-(chlorosulfonyl)phenyl]ethyl carbamate and 0.65 mL of pyridine were added at room temperature, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was diluted with ethyl acetate, washed twice with 1N hydrochloric acid and once with saturated brine, and then dried and filtered over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. The resulting residue was suspended and washed with diethyl ether-hexane (1:1), and then filtered to obtain the title compound (710 mg) as a beige solid. MS(ESI)m / z: 467.3[MH] -

[0518] (23-2) 4-(2-aminoethyl)-N-(3-cyano-4-ethyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Reference compound 23)

[0519] [ka]

[0520] Reference compound 23-1 (702 mg) was mixed with 4 M hydrogen chloride / 1,4-dioxane solution (7.0 mL) at room temperature. After stirring at the same temperature for 16 hours, the reaction mixture was diluted with diethyl ether, the solid was suspended and washed, and then filtered to obtain the title compound (610 mg) as a beige solid. MS(ESI)m / z:369.1[M+H] +

[0521] Example 1 (1-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 1)

[0522] [ka]

[0523] HATU (46 mg) was added at room temperature to a solution of Reference Compound 4 (50 mg), Reference Compound 5 (38 mg), and triethylamine (0.042 mL) in N,N-dimethylformamide (2.0 mL), and the mixture was stirred at the same temperature for 5 hours. Under ice cooling, water was added to the reaction mixture, and it was extracted twice with chloroform. The combined organic layer was washed twice with water, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution - acetonitrile) to obtain the title compound (49 mg) as a pale yellow powder. MS(ESI) m / z: 823.5[M+H]+

[0524] Example 2 (2-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 2)

[0525] [ka]

[0526] A mixture of Reference Compound 12 (78 mg), Reference Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture and stirred, and the resulting solid was filtered off. The title compound (86 mg) was obtained as a white solid by purification using silica gel column chromatography (chloroform:methanol = 100:0 to 95:5). MS(ESI) m / z: 841.6 [M+H] +

[0527] Example 3 (3-1) Methyl [(6S)-4-{3'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 3)

[0528] [ka]

[0529] A mixture of Reference Compound 13 (80 mg), Reference Compound 5 (56 mg), N,N-diisopropylethylamine (0.052 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3 mL) at room temperature for 2 hours. Water was added to the reaction mixture and stirred, and the resulting solid was filtered off. Purification by silica gel column chromatography (chloroform:methanol = 100:0~95:5) yielded the title compound (115 mg) as a pale yellow solid. MS(ESI)m / z: 857.6, 859.6 [M+H] +

[0530] Example 4 (4-1) t-butyl (3R)-1-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}pyrrolidine-3-carboxylate (Example compound 4-1)

[0531] [ka]

[0532] Under a nitrogen atmosphere, Reference Compound 1 (200 mg), t-butylpyrrolidine-3-carboxylate (99 mg), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate (40 mg), potassium phosphate (256 mg), and water (0.043 mL) were heated under reflux for 100 minutes in tetrahydrofuran (1.0 mL) solvent. The reaction mixture was allowed to cool, diluted with ethyl acetate, and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered through activated carbon, washed with methanol and tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (266 mg) as a pale yellow powder. MS(ESI)m / z:550.3[M+H] +

[0533] (4-2)(3R)-1-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}pyrrolidine-3-carboxylic acid (Example compound 4-2)

[0534] [ka]

[0535] To a solution of Compound 4-1 (266 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically removed three times with chloroform-toluene. The residue was dissolved in ethyl acetate, and N,N-diisopropylethylamine (0.30 mL) was added gradually while stirring. Hexane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and washed with an ethyl acetate-hexane mixture (2:1) to obtain the title compound (181 mg) as a yellow powder. MS(ESI)m / z:494.3[M+H] +

[0536] (4-3)methyl [(6S)-4-(4-{(3R)-3-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyrrolidine-1-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 4)

[0537] [ka]

[0538] In Example 2, the title compound (111 mg) was obtained as a yellow powder by using Example Compound 4-2 (74 mg) instead of Reference Example Compound 12 and carrying out the same reaction and treatment as in (2-1). MS(ESI)m / z:816.3[M+H] +

[0539] Example 5 (5-1) Methyl {(6S)-4-[4-(3-hydroxypropane-1-in-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 5-1)

[0540] [ka]

[0541] A mixture of reference compound 1 (100 mg), propargyl alcohol (27 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 12 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (21 mg), potassium phosphate (102 mg), and tetrahydrofuran (1.2 mL) is used. The mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere and microwave irradiation. After diluting the reaction mixture with ethyl acetate, it was washed twice with saturated saline solution and water (1:1) and once with saturated saline solution. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10, pre-column: NH silica gel) to obtain the title compound (63 mg) as a pale yellow viscous substance. MS(ESI) m / z: 435.3[M+H] +

[0542] (5-2) Methyl {(6S)-2,3,9-trimethyl-4-[4-(3-oxopropa-1-in-1-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 5-2)

[0543] [ka]

[0544] 60 mg of Example Compound 5-1 in 1.2 mL of dichloromethane was mixed with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Dess-Martin reagent, 71 mg) and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate solution and saturated sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with saturated sodium bicarbonate solution, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (59 mg) as a pale yellow viscous substance. MS(ESI) m / z: 433.3[M+H] +

[0545] (5-3) Methyl [(6S)-4-(4-{3-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)amino]-3-oxopropa-1-in-1-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 5)

[0546] [ka]

[0547] To a solution of Example Compound 5-2 (57 mg) and 2-methyl-buta-2-ene (0.021 mL) in acetonitrile (3.0 mL), a solution of 80% sodium chlorite (18 mg) and sodium dihydrogen phosphate (19 mg) in water (1.0 mL) was added and stirred at room temperature for 30 minutes. 2-methyl-buta-2-ene (0.021 mL), 80% sodium chlorite (18 mg), and sodium dihydrogen phosphate (19 mg) were added to the reaction mixture at room temperature and stirred for another 30 minutes at the same temperature. After concentrating the reaction mixture under reduced pressure, ethanol was added and it was concentrated again under reduced pressure. To the resulting residue, Reference Example Compound 5 (47 mg), N,N-diisopropylethylamine (0.11 mL), and N,N-dimethylformamide (2.0 mL) were added at room temperature, and finally HATU (57 mg) was added. The mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed three times with saturated saline solution and water (1:1), and once with saturated saline solution. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (17 mg) as a beige powder. MS(ESI)m / z:771.4[M+H] +

[0548] Example 6 (6-1) Methyl {(6S)-4-[4-(3-aminopropa-1-in-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 6-1)

[0549] [ka]

[0550] A mixture of Reference Compound 1 (25 mg), propargylamine (0.019 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 3 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (5 mg), potassium phosphate (64 mg), and tetrahydrofuran (0.3 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 95:5~90:10) to obtain the title compound (15 mg) as a beige powder. MS(ESI) m / z: 434.3[M+H] +

[0551] (6-2) Methyl {(6S)-4-[4-(3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]benzamide}propa-1-in-1-yl)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example Compound 6)

[0552] [ka]

[0553] To a solution of Example Compound 6-1 (14 mg) and Reference Example Compound 6 (13 mg) in N,N-dimethylformamide (0.4 mL), N,N-diisopropylethylamine (0.11 mL) and HATU (15 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (20 mg) as a white powder. MS(ESI)m / z:771.4[M+H] +

[0554] Example 7 (7-1) 7-Bromo-3-chloro-1H-indole (Example Compound 7-1)

[0555] [ka]

[0556] To a solution of 7-bromo-1H-indole (500 mg) in N,N-dimethylformamide (5.0 mL), N-chlorosuccinimide (358 mg) was added at room temperature and the mixture was stirred at the same temperature for 2 hours. Saturated sodium bicarbonate solution and saturated sodium thiosulfate solution were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5~90:10) to obtain the title compound (577 mg) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.09(1H,t,J=7.77Hz),7.24-7.27(1H,m),7.41(1H,dd,J=7.71,0.64Hz),7.59(1H,dt,J=7.96,0.77Hz),8.25(1H,brs)

[0557] (7-2) 3-chloro-1H-indole-7-amine (Example compound 7-2)

[0558] [ka]

[0559] In Reference Example 9, the title compound (163 mg) was obtained as a light brown solid by performing the same reaction and treatment using Example Compound 7-1 (570 mg) instead of Reference Example Compound 8. MS(ESI)m / z: 167.0, 169.0 [M+H] +

[0560] (7-3) Methyl [(6S)-4-{4'-[({4-[(3-chloro-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 7)

[0561] [ka]

[0562] To a solution of Example Compound 7-2 (18 mg) and Reference Example Compound 10 (50 mg) in tetrahydrofuran (2.0 mL), pyridine (0.060 mL) was added at room temperature and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed once with 1N hydrochloric acid and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (37 mg) as a white solid. MS(ESI)m / z:818.4,820.4[M+H] +

[0563] Example 8 (8-1)7-bromo-3-chloro-4-methyl-1H-indole (Example compound 8-1)

[0564] [ka]

[0565] In Example 7, 7-bromo-4-methyl-1H-indole (200 mg) was used instead of 7-bromo-1H-indole, and the same reaction and treatment as in (7-1) was carried out to obtain the title compound (212 mg) as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ ppm 2.75(3H,d,J=0.64Hz),6.77(1H,d,J=7.87Hz),7.20(1H,d,J=2.70Hz),7.24(1H,d,J=7.71Hz),8.22(1H,brd,J=1.67Hz)

[0566] (8-2) 3-chloro-4-methyl-1H-indole-7-amine (Example compound 8-2)

[0567] [ka]

[0568] In Reference Example 9, the title compound (56 mg) was obtained as a light brown solid by performing the same reaction and treatment using Example Compound 8-1 (205 mg) instead of Reference Example Compound 8. MS(ESI)m / z: 181.0, 183.0 [M+H] +

[0569] (8-3) Methyl [(6S)-4-{4'-[({4-[(3-chloro-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 8)

[0570] [ka]

[0571] In Example 7, instead of Example Compound 7-2, Example Compound 8-2 (20 mg) and Reference Example Compound 10 (50 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (44 mg) as a gray powder. MS(ESI)m / z:832.4,834.4[M+H] +

[0572] Example 9 (9-1)7-bromo-1H-indole-3-carbonitride (Example compound 9-1)

[0573] [ka]

[0574] In Reference Example 8, 7-bromo-1H-indole (500 mg) was used instead of Reference Example Compound 7, and the same reaction and treatment were carried out to obtain the title compound (548 mg) as a light brown solid. 1 H NMR(400MHz,CDCl3)δ ppm 7.20(1H,t,J=7.83Hz),7.50(1H,dd,J=7.71,0.77Hz),7.73(1H,d,J=7.96Hz),7.80(1H,d,J=2.95Hz),8.84(1H,brs)

[0575] (9-2) 7-amino-1H-indole-3-carbonitrile (Example compound 9-2)

[0576] [ka]

[0577] In Reference Example 9, the title compound (322 mg) was obtained as a light brown solid by using Example Compound 9-1 (542 mg) instead of Reference Example Compound 8 and performing the same reaction and treatment. 1 H NMR(400MHz,DMSO-d6)δ ppm 5.33(2H,s),6.47(1H,dd,J=7.58,0.90Hz),6.81(1H,dd,J=7.96,0.90Hz),6.94(1H,t,J=7.77Hz),8.13(1H,s),11.73(1H,brs)

[0578] (9-3) Methyl [(6S)-4-{4'-[({4-[(3-cyano-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 9)

[0579] [ka]

[0580] In Example 7, instead of Example Compound 7-2, Example Compound 9-2 (15 mg) and Reference Example Compound 10 (44 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (40 mg) as a beige powder. MS(ESI)m / z:809.4[M+H] +

[0581] Example 10 (10-1) 4-methyl-1H-indole-7-amine (Example compound 10-1)

[0582] [ka]

[0583] In Reference Example 9, the title compound (29 mg) was obtained as a light brown solid by using Reference Example Compound 7 (92 mg) instead of Reference Example Compound 8 and performing the same reaction and treatment. MS(ESI)m / z:147.1[M+H] +

[0584] (10-2) Methyl [(6S)-2,3,9-trimethyl-4-{4'-[({4-[(4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 10)

[0585] [ka]

[0586] In Example 7, instead of Example Compound 7-2, Example Compound 10-1 (28 mg) and Reference Example Compound 10 (120 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (107 mg) as a beige powder. MS(ESI)m / z:798.5[M+H] +

[0587] Example 11 (11-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 11)

[0588] [ka]

[0589] A mixture of Reference Compound 4 (75 mg), Reference Compound 11 (65 mg), N,N-diisopropylethylamine (0.078 mL), and HATU (86 mg) was stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture and stirred, and the resulting solid was filtered off. Purification by silica gel column chromatography (chloroform:methanol = 100:0~95:5) yielded the title compound (115 mg) as a pale yellow solid. MS(ESI)m / z:837.4[M+H] +

[0590] Example 12 (12-1) Methyl 3-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]benzoate (Example compound 12-1)

[0591] [ka]

[0592] Reference compound 9 (200 mg), methyl 3-(chlorosulfonyl)benzoate (302 mg), and triethylamine (0.33 mL) were stirred in chloroform (5.0 mL) at room temperature for 7 hours. Water was added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 70:30~30:70) and silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (190 mg) as a pale yellow solid. MS(ESI) m / z: 370.3[M+H] +

[0593] (12-2)N-(3-cyano-4-methyl-1H-indole-7-yl)-3-(hydroxymethyl)benzene-1-sulfonamide (Example compound 12-2)

[0594] [ka]

[0595] A solution of Example Compound 12-1 (190 mg) in tetrahydrofuran (5.0 mL) was cooled to 0°C. 2M lithium borohydride / tetrahydrofuran solution (0.77 mL) and methanol (0.063 mL) were added, and the mixture was stirred for 4 hours while allowing it to rise naturally to room temperature. Another 2M lithium borohydride / tetrahydrofuran solution (0.77 mL) was added, and the mixture was stirred at room temperature for 3 hours. 1N hydrochloric acid was gradually added to the reaction mixture and stirred, followed by the addition of chloroform and stirring. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0-95:5) to obtain the title compound (124 mg) as a white solid. MS(ESI) m / z: 342.1[M+H]+

[0596] (12-3)3-(azidomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Example compound 12-3)

[0597] [ka]

[0598] To a solution of Compound 12-2 (124 mg) in tetrahydrofuran (5.0 mL), 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (207 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (111 mg) were added and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction mixture and stirred. The organic layer was separated, washed twice with saline solution, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20~50:50) to obtain the title compound (69 mg) as a white solid. MS(ESI) m / z: 367.1[M+H] +

[0599] (12-4)3-(aminomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Example compound 12-4)

[0600] [ka]

[0601] Compound 12-3 (69 mg), triphenylphosphine (64 mg), and water (0.5 mL) were stirred in tetrahydrofuran (5.0 mL) at 50°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with chloroform, filtered, and dried to obtain the title compound (60 mg) as a white solid. MS(ESI)m / z:341.1[M+H] +

[0602] (12-5)methyl [(6S)-4-{4'-[({3-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 12)

[0603] [ka]

[0604] In Example 11, the title compound was obtained as a white solid by using Example Compound 12-4 instead of Reference Compound 11 and carrying out the same reaction and treatment as in (11-1). MS(ESI)m / z:823.4[M+H] +

[0605] Example 13 (13-1) 7-bromo-6-methyl-1H-indole (Example compound 13-1)

[0606] [ka]

[0607] In Reference Example 7, the title compound (1108 mg) was obtained as a white solid by performing the same reaction and treatment using 2-bromo-3-nitrotoluene (2160 mg) instead of 1-bromo-4-methyl-2-nitrobenzene. 1 H NMR(400MHz,CDCl3)δ ppm 2.52(3H,s),6.58(1H,dd,J=3.21,2.18Hz),7.00(1H,d,J=7.96Hz),7.19(1H,dd,J=3.08,2.44Hz),7.46(1H,d,J=7.96Hz),8.27(1H,brs)

[0608] (13-2) 7-bromo-6-methyl-1H-indole-3-carbonitride (Example compound 13-2)

[0609] [ka]

[0610] In Reference Example 8, the title compound (461 mg) was obtained as a beige solid by performing the same reaction and treatment using Example Compound 13-1 (500 mg) instead of Reference Example Compound 7. 1 H NMR(400MHz,CDCl3)δ ppm 2.54(3H,s),7.19(1H,d,J=8.1Hz),7.61(1H,d,J=8.1Hz),7.72(1H,d,J=2.8Hz),8.72(1H,brs)

[0611] (13-3) 7-amino-6-methyl-1H-indole-3-carbonitride (Example compound 13-3)

[0612] [ka]

[0613] In Reference Example 9, the title compound (146 mg) was obtained as a white solid by performing the same reaction and treatment using Example Compound 13-2 (455 mg) instead of Reference Example Compound 8. MS(ESI)m / z:172.1[M+H] +

[0614] (13-4)methyl [(6S)-4-{4'-[({4-[(3-cyano-6-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 13)

[0615] [ka]

[0616] In Example 7, instead of Example Compound 7-2, Example Compound 13-3 (17 mg) and Reference Example Compound 10 (60 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (34 mg) as a white powder. MS(ESI)m / z:823.5[M+H] +

[0617] Example 14 (14-1) Methyl [(6S)-4-{4'-[({4-[(4-chloro-3-cyano-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 14)

[0618] [ka]

[0619] In Example 13, 1-bromo-4-chloro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene, and the same reaction and treatment as in (13-1)-(13-4) was carried out to obtain the title compound as a white solid. MS(ESI)m / z:843.4,845.5[M+H] +

[0620] Example 15 (15-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methoxy-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 15)

[0621] [ka]

[0622] In Example 13, 4-bromo-3-nitroanisole was used instead of 2-bromo-3-nitrotoluene, and the same reaction and treatment as in (13-1)-(13-4) was carried out to obtain the title compound as a purple solid. MS(ESI)m / z:839.5[M+H] +

[0623] Example 16 (16-1) Methyl [(6S)-4-{4'-[({4-[(2,3-dimethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 16)

[0624] [ka]

[0625] In Example 7, instead of Example Compound 7-2, 2,3-dimethyl-1H-indole-7-amine (17 mg) and Reference Example Compound 10 (50 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (22 mg) as a brown solid. MS(ESI)m / z:812.5[M+H] +

[0626] Example 17 (17-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-fluoro-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 17)

[0627] [ka]

[0628] In Example 13, 1-bromo-4-fluoro-2-nitrobenzene was used instead of 2-bromo-3-nitrotoluene, and the same reaction and treatment as in (13-1)-(13-4) was carried out to obtain the title compound as a beige powder. MS(ESI)m / z:827.5[M+H] +

[0629] Example 18 (18-1) Methyl [(6S)-4-(4'-{[(4-{[3-cyano-4-(trifluoromethyl)-1H-indole-7-yl]sulfamoyl}phenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 18)

[0630] [ka]

[0631] In Example 13, 1-bromo-2-nitro-4-trifluoromethylbenzene was used instead of 2-bromo-3-nitrotoluene, and the same reaction and treatment as in (13-1)-(13-4) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:877.5[M+H] +

[0632] Example 19 (19-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-5-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 19)

[0633] [ka]

[0634] In Example 13, 3-bromo-4-nitrotoluene was used instead of 2-bromo-3-nitrotoluene, and the same reaction and treatment as in (13-1)-(13-4) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:823.5[M+H] +

[0635] Example 20 (20-1) Methyl 5-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]pyridine-2-carboxylate (Example compound 20-1)

[0636] [ka]

[0637] Reference compound 9 (300 mg), methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (454 mg), and pyridine (0.71 mL) were stirred in tetrahydrofuran (5.0 mL) at room temperature for 4 hours. Ethyl acetate and 1N hydrochloric acid were added to the reaction mixture and stirred, and the resulting solid was filtered off. Saturated sodium bicarbonate solution and tetrahydrofuran were added to the solid and stirred, then chloroform was added, the aqueous layer was removed with a phase separator, and the organic layer was concentrated under reduced pressure. After suspending and washing the residue with diethyl ether, the title compound (210 mg) was obtained as a yellow solid by filtration. MS(ESI)m / z:371.1[M+H] +

[0638] (20-2)6-(azidomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)pyridine-3-sulfonamide (Example compound 20-2)

[0639] [ka]

[0640] Under a nitrogen atmosphere, a suspension of Example Compound 20-1 (210 mg) in tetrahydrofuran (5.0 mL) was mixed with 1.14 mL of 2 M lithium borohydride / tetrahydrofuran solution and stirred at room temperature for 5 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and stirred, followed by chloroform and stirring. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain a white solid (75 mg). This solid, along with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (125 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.066 mL), was mixed in tetrahydrofuran (5.0 mL) and stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution and chloroform were added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 70:30 to 30:70) to obtain the title compound (63 mg) as a white solid. MS(ESI) m / z: 368.2[M+H] +

[0641] (20-3)6-(aminomethyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)pyridine-3-sulfonamide (Example compound 20-3)

[0642] [ka]

[0643] In Example 12, the title compound (24 mg) was obtained as a white solid by using Example Compound 20-2 (63 mg) instead of Example Compound 12-3 and performing the same reaction and treatment as in (12-4). MS(ESI)m / z:342.1[M+H] +

[0644] (20-4)methyl [(6S)-4-{4'-[({5-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]pyridine-2-yl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 20)

[0645] [ka]

[0646] In Example 11, the title compound was obtained as a pale yellow solid by using Example Compound 20-3 instead of Reference Example Compound 11 and carrying out the same reaction and treatment as in (11-1). MS(ESI)m / z:824.3[M+H] +

[0647] Example 21 (21-1) t-butyl 4-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (Example compound 21-1)

[0648] [ka]

[0649] Under an argon stream, Reference Compound 1 (500 mg), N-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (447 mg), palladium acetate (7 mg), S-phos (99 mg), potassium fluoride (210 mg), and water (0.078 mL) were heated under reflux in tetrahydrofuran (5.0 mL) for 7 hours. The reaction mixture was filtered through diatomaceous earth using ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 70:30~20:80) to obtain the title compound (680 mg) as a pale yellow solid. MS(ESI) m / z: 562.5[M+H] +

[0650] (21-2) Methyl {(6S)-2,3,9-trimethyl-4-[4-(1,2,3,6-tetrahydropyridine-4-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate hydrochloride (Example compound 21-2)

[0651] [ka]

[0652] To a methanol (0.5 mL) solution of Example Compound 21-1 (217 mg), 4 M hydrogen chloride / 1,4-dioxane solution (2.0 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was suspended and washed with diisopropyl ether, filtered, and dried to obtain the title compound (198 mg) as a yellow solid. MS(ESI)m / z:462.2[M+H] +

[0653] (21-3) Methyl [(6S)-4-(4-{1-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1,2,3,6-tetrahydropyridine-4-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 21)

[0654] [ka]

[0655] To a solution of triphosgene (22 mg) in tetrahydrofuran (3.0 mL), reference compound 5 (68 mg) and N,N-diisopropylethylamine (0.11 mL) were added and the mixture was stirred at room temperature for 15 minutes. Subsequently, example compound 21-2 (100 mg) and N,N-dimethylformamide (0.5 mL) were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and stirred. The mixture was extracted three times with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~95:5), washed with diethyl ether, filtered, and dried to obtain the title compound (60 mg) as a milky white powder. MS(ESI)m / z:828.4[M+H] +

[0656] Example 22 (22-1)7-bromo-1H-indole-4-carbonitrili (Example compound 22-1)

[0657] [ka]

[0658] In Reference Example 7, 4-bromo-3-benzonitrile (2270 mg) was used instead of 1-bromo-4-methyl-2-nitrobenzene, and the same reaction and treatment was carried out to obtain the title compound (540 mg) as a pale yellow solid. 1H NMR(400MHz,CDCl3)δ ppm 6.86(1H,dd,J=3.21,2.18Hz),7.36(1H,d,J=8.35Hz),7.41(1H,d,J=7.83Hz),7.46(1H,t,J=3.21Hz),8.65(1H,brs)

[0659] (22-2) 7-amino-1H-indole-4-carbonitrile (Example compound 22-2)

[0660] [ka]

[0661] In Reference Example 9, the title compound (53 mg) was obtained as a pale yellow solid by using Example Compound 22-1 (100 mg) instead of Reference Example Compound 8 and performing the same reaction and treatment. 1 H NMR(400MHz,DMSO-d6)δ ppm 6.06(2H,s),6.34-6.41(2H,m),7.22(1H,d,J=7.96Hz),7.49(1H,t,J=2.83Hz),11.15(1H,brs)

[0662] (22-3) Methyl [(6S)-4-{4'-[({4-[(4-cyano-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 22)

[0663] [ka]

[0664] In Example 7, instead of Example Compound 7-2, Example Compound 22-2 (29 mg) and Reference Example Compound 10 (80 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (26 mg) as a white powder. MS(ESI)m / z:809.4[M+H] +

[0665] Example 23 (23-1) 7-bromo-1H-indole-3,4-dicarbonitrine (Example compound 23-1)

[0666] [ka]

[0667] In Reference Example 8, the title compound (48 mg) was obtained as a pale yellow solid by performing the same reaction and treatment using Example Compound 22-1 (100 mg) instead of Reference Example Compound 7. MS(ESI)m / z: 246.0, 248.0 [M+H] +

[0668] (23-2) 7-amino-1H-indole-3,4-dicarbonitrine (Example compound 23-2)

[0669] [ka]

[0670] In Reference Example 9, the title compound (10 mg) was obtained as a pale yellow solid by performing the same reaction and treatment using Example Compound 23-1 (45 mg) instead of Reference Example Compound 8. MS(ESI)m / z:183.1[M+H] +

[0671] (23-3) Methyl [(6S)-4-{4'-[({4-[(3,4-dicyano-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 23)

[0672] [ka]

[0673] In Example 7, instead of Example Compound 7-2, Example Compound 23-2 (9.4 mg) and Reference Example Compound 10 (72 mg) were used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (15 mg) as a pale yellow powder. MS(ESI)m / z:834.5[M+H] +

[0674] Example 24 (24-1)N-(3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}propyl)-2,2,2-trifluoroacetamide (Example compound 24-1)

[0675] [ka]

[0676] In Example 20, 4-[3-(trifluoroacetamido)propyl]benzenesulfonyl chloride was used instead of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate, and the title compound was obtained as a brown powder by the same reaction and treatment as in (20-1). MS(ESI)m / z:465.2[M+H] +

[0677] (24-2) 4-(3-aminopropyl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Example compound 24-2)

[0678] [ka]

[0679] Compound 24-1 (610 mg), potassium carbonate (545 mg), and water (0.8 mL) were stirred in methanol (8.0 mL) at room temperature for 2 hours. Methanol was removed under reduced pressure, and water was added and the mixture was stirred. 1N hydrochloric acid (5 mL) was added and the mixture was stirred. The resulting solid was filtered off. The mixture was washed with water and dried to obtain a gray solid. Potassium carbonate (273 mg), water (0.5 mL), and methanol (5.0 mL) were added to this solid and the mixture was heated under reflux for 6 hours. Methanol was removed under reduced pressure, and water was added and the mixture was stirred. 1N hydrochloric acid was added and the mixture was stirred. The resulting solid was filtered off. The mixture was washed with water, filtered, and dried to obtain the title compound (453 mg) as a gray solid. MS(ESI)m / z:369.2[M+H] +

[0680] (24-3) Methyl [(6S)-4-{4'-[(3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}propyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 24)

[0681] [ka]

[0682] In Example 11, the title compound was obtained as a beige solid by using Example Compound 24-2 instead of Reference Compound 11 and carrying out the same reaction and treatment as in (11-1). MS(ESI)m / z:851.7[M+H] +

[0683] Example 25 (25-1) Methyl {(6S)-4-[4'-({[4-(chlorosulfonyl)-3-fluorophenyl]methyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 25-1)

[0684] [ka]

[0685] In Reference Example 10, the title compound was obtained as a pale yellow powder by using 4-bromo-3-fluorophenylmethaneamine hydrochloride instead of 4-bromobenzylamine and carrying out the same reaction and treatment as in (10-1)-(10-3). MS(ESI)m / z:688.4[M-Cl+H2O] +

[0686] (25-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]-3-fluorophenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 25)

[0687] [ka]

[0688] In Example 7, Reference Compound 9 (26 mg) was used instead of Example Compound 7-2, and Example Compound 25-1 (97 mg) was used instead of Example Compound 10. By performing the same reaction and treatment as in (7-3), the title compound (69 mg) was obtained as a beige powder. MS(ESI)m / z:841.5[M+H] +

[0689] Example 26 (26-1) Methyl [(6S)-4-(4'-{[(1R)-1-(4-bromophenyl)ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 26-1)

[0690] [ka]

[0691] A mixed solution of reference compound 4 (100 mg), (1R)-1-(4-bromophenyl)ethaneamine (48 mg), N,N-diisopropylethylamine (0.10 mL), and HATU (91 mg) in N,N-dimethylformamide (2.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed three times with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (156 mg) as a crude pale yellow powder. MS(ESI)m / z:682.4,684.4[M+H] +

[0692] (26-2) Methyl {(6S)-4-[4'-({(1R)-1-[4-(benzylsulfanyl)phenyl]ethyl}carbamoyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 26-2)

[0693] [ka]

[0694] A mixture of Example Compound 26-1 (133 mg), benzyl mercaptan (0.028 mL), N,N-diisopropylethylamine (0.10 mL), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (Xantphos, 23 mg), tris(dibenzylideneacetone)dipalladium (18 mg), toluene (2.0 mL), and tetrahydrofuran (0.70 mL) was stirred at 150°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, the reaction solution was purified directly by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (126 mg) as a pale yellow powder. MS(ESI) m / z: 726.5[M+H] +

[0695] (26-3) Methyl [(6S)-4-(4'-{[(1R)-1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 26)

[0696] [ka]

[0697] To a solution of Example Compound 26-2 (124 mg) in acetonitrile (2.5 mL) and 2N hydrochloric acid (0.50 mL), N-chlorosuccinimide (80 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Saturated saline solution and water (1:1) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline solution, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the obtained residue and a solution of Reference Example Compound 9 (33 mg) in tetrahydrofuran (5.0 mL), pyridine (0.14 mL) was added at room temperature, and the mixture was stirred at the same temperature for 16 hours. Saturated saline solution and water (1:1) were added to the reaction mixture, and the mixture was extracted once with chloroform-methanol and twice with chloroform. The combined organic layer was dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform:methanol = 90:10 to 50:50), and then again by silica gel column chromatography (chloroform:methanol = 98:2 to 90:10) to obtain a crude product of the title compound. The entire crude product was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution - acetonitrile) to obtain the title compound (16 mg) as a white powder. MS(ESI) m / z: 837.5[M+H] +

[0698] Example 27 (27-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]-2-fluorophenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 27)

[0699] [ka]

[0700] In Example 25, 4-bromo-2-fluorophenylmethaneamine hydrochloride was used instead of 4-bromo-3-fluorophenylmethaneamine hydrochloride, and the same reaction and treatment as in (25-1)-(25-2) was carried out to obtain the title compound as a beige powder. MS(ESI)m / z:841.5[M+H] +

[0701] Example 28 (28-1) Methyl [(6S)-4-{4'-[(1-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}-2-hydroxyethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 28)

[0702] [ka]

[0703] In Example 25, 2-amino-2-(4-bromophenyl)ethanol was used instead of 4-bromo-3-fluorophenylmethaneamine hydrochloride, and the same reaction and treatment as in (25-1)-(25-2) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:853.5[M+H] +

[0704] Example 29 (29-1) 3,4-dimethyl-1H-indole-7-amine (Example compound 29-1)

[0705] [ka]

[0706] Under a nitrogen stream, 7-bromo-3,4-dimethyl-1H-indole (443 mg), benzophenone imine (501 mg), 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (5.3 mL), and [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 47 mg) were heated under reflux in tetrahydrofuran (3.0 mL) for 7 hours. Saturated ammonium chloride aqueous solution and chloroform were added to the reaction mixture and stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue and hydroxylamine hydrochloride (344 mg) and sodium acetate (487 mg) were stirred in a methanol (3.0 mL)-tetrahydrofuran (3.0 mL) mixed solvent at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated baking soda water and chloroform were added, and the mixture was stirred. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (279 mg) as a gray solid. MS(ESI) m / z: 161.2[M+H] +

[0707] (29-2) Methyl [(6S)-4-{4'-[({4-[(3,4-dimethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 29)

[0708] [ka]

[0709] Example compound 29-1 (19 mg), reference example compound 10 (70 mg), and pyridine (0.041 mL) were stirred in tetrahydrofuran (3.0 mL) at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and azeotropically diluted with toluene. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) and silica gel column chromatography (ethyl acetate:methanol = 100:0 to 95:5) to obtain the title compound (57 mg) as a pale yellow solid. MS(ESI) m / z: 812.7[M+H] +

[0710] Example 30 (30-1) Methyl {(6S)-4-[4'-(4-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}piperidine-1-carbonyl)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example Compound 30)

[0711] [ka]

[0712] In Example 25, 4-(4-bromophenyl)piperidine hydrochloride was used instead of 4-bromo-3-fluorophenylmethaneamine hydrochloride, and the same reaction and treatment as in (25-1)-(25-2) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:877.6[M+H] +

[0713] Example 31 (31-1) t-butyl (3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}prop-2-in-1-yl)carbamate (Example compound 31-1)

[0714] [ka]

[0715] A mixture of reference compound 14 (300 mg), N-(t-butoxycarbonyl)propargylamine (239 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 37 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (61 mg), potassium phosphate (490 mg), and tetrahydrofuran (4.0 mL) was stirred at 120°C for 1 hour under a nitrogen atmosphere and microwave irradiation. Saturated saline solution and water (1:1) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline solution, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 98:2 to 95:5), and then further purified by NH silica gel column chromatography (chloroform:methanol = 95:5 to 50:50) to obtain the title compound (209 mg) as a pale yellow powder. MS(ESI) m / z: 465.3[M+H] +

[0716] (31-2) 4-(3-aminopropa-1-in-1-yl)-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide hydrochloride (Example compound 31-2)

[0717] [ka]

[0718] Compound 31-1 (205 mg) was added to a 4M hydrogen chloride / 1,4-dioxane solution (6.0 mL) at room temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and filtered to obtain the title compound (150 mg) as a brown solid. MS(ESI)m / z:365.2[M+H] +

[0719] (31-3) Methyl [(6S)-4-{4'-[(3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}propa-2-in-1-yl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 31)

[0720] [ka]

[0721] To a solution of Example Compound 31-2 (65 mg) and Reference Example Compound 4 (80 mg) in N,N-dimethylformamide (1.6 mL), N,N-diisopropylethylamine (0.083 mL) and HATU (73 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with methanol and added to ethyl acetate and saturated brine-water (1:1). After filtering off a small amount of insoluble matter, the filtrate was separated. The organic layer was washed twice with saturated brine-water (1:1) and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 95:5~50:50, pre-column:silica gel) to obtain the title compound (103 mg) as a white powder. MS(ESI)m / z:847.5[M+H] +

[0722] Example 31 (32-1) Methyl 4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Example compound 32-1)

[0723] [ka]

[0724] Reference compound 2 (150 mg), 4-(methoxycarbonyl)phenylboronic acid (81 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl aminobiphenyl palladium chloride pre-catalyst (15 mg), sodium carbonate (79 mg), 1,4-dioxane (3.0 mL), and water (1.0 mL) were mixed and stirred at 100°C for 20 minutes under microwave irradiation. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 80:20~0:100) to obtain the title compound (161 mg) as a white powder. MS(ESI) m / z: 457.3[M+H] +

[0725] (32-2)N-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-4'-[(6S)-2,3,6,9-tetramethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 32)

[0726] [ka]

[0727] To a methanol (3.0 mL) solution of Example Compound 32-1 (73 mg), 0.32 mL of 1 N sodium hydroxide aqueous solution was added and the mixture was stirred at room temperature for 9 hours. 1 N hydrochloric acid was added to the reaction mixture and stirred, then the mixture was concentrated under reduced pressure. The resulting solid, along with Reference Example Compound 5 (60 mg), N,N-diisopropylethylamine (0.082 mL), and HATU (72 mg), were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 1 hour. Water was added to the reaction mixture and stirred, and the resulting solid was filtered off. Purification by silica gel column chromatography (chloroform:methanol = 100:0~95:5) yielded the title compound (100 mg) as a white solid. MS(ESI) m / z: 765.6[M+H]+

[0728] Example 33 (33-1) Methyl 7-bromo-1H-indole-4-carboxylate (Example compound 33-1)

[0729] [ka]

[0730] To a tetrahydrofuran solution (30.0 mL) of methyl 4-bromo-3-nitrobenzoate (2600 mg), a 1 M vinyl magnesium bromide / tetrahydrofuran solution (25.0 mL) was added over 5 minutes at -78°C. After stirring at the same temperature for 1 hour, saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the temperature was raised to room temperature. After liquid-liquid separation, the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10) to obtain the title compound (1223 mg) as a white solid. MS(ESI) m / z: 254.1, 256.0 [M+H] +

[0731] (33-2) Methyl 7-bromo-3-cyano-1H-indole-4-carboxylate (Example compound 33-2)

[0732] [ka]

[0733] To a 4.0 mL solution of compound 33-1 (1000 mg) in N,N-dimethylformamide, phenylphosphonyl dichloride (1.0 mL) was added at room temperature. After stirring at 100°C for 20 minutes, N,N-dimethylformamide (4.0 mL) was added, and the mixture was stirred for a further 40 minutes at 100°C. Hydroxylamine hydrochloride (547 mg) was added, and the mixture was heated and stirred at 100°C for 2 hours and then at 140°C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with saturated sodium bicarbonate solution and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (703 mg) as a crude brown solid. MS(ESI)m / z:279.2,281.2[M+H] +

[0734] (33-3)7-bromo-4-(hydroxymethyl)-1H-indole-3-carbonitride (Example compound 33-3)

[0735] [ka]

[0736] To a suspension of compound 33-2 (391 mg) in tetrahydrofuran (16.0 mL), 1.70 mL of 2.5 M lithium aluminum hydride / tetrahydrofuran solution was added dropwise under ice cooling. After stirring for 10 minutes at the same temperature, 1 N hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was washed with chloroform and filtered to obtain the title compound (221 mg) as a gray solid. MS(ESI)m / z: 233.0, 235.0 [M-OH] + ; 1H NMR(400MHz,DMSO-d6)δ ppm 4.94(2H,d,J=5.27Hz),5.33(1H,t,J=5.33Hz),7.10-7.27(1H,m),7.48(1H,d,J=7.83Hz),8.31(1H,s),12.44(1H,brs)

[0737] (33-4) 7-[(diphenylmethylidene)amino]-4-(hydroxymethyl)-1H-indole-3-carbonitrile (Example compound 33-4)

[0738] [ka]

[0739] In the first example, a mixture of compound 33-3 (267 mg), benzophenone imine (270 mg), [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)dichloropalladium(II) (Pd-PEPPSI-IPent catalyst, 26 mg), and tetrahydrofuran (7.0 mL) was mixed with 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) at room temperature and stirred at 140 °C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. Then, Pd-PEPPSI-IPent catalyst (85 mg) and 1.3 M lithium bis(trimethylsilyl)amide / tetrahydrofuran solution (2.9 mL) were added and stirred at 160 °C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. After cooling to room temperature, water was added to the reaction mixture and it was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2), and then again by NH silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (59 mg) as a pale yellow solid. MS(ESI)m / z:352.2[M+H] +

[0740] (33-5) 7-amino-4-(hydroxymethyl)-1H-indole-3-carbonitride (Example compound 33-5)

[0741] [ka]

[0742] Compound 33-4 (57 mg) was dissolved in tetrahydrofuran (1.0 mL)-methanol (1.0 mL), and hydroxylamine hydrochloride (28 mg) and sodium acetate (40 mg) were added at room temperature. The mixture was stirred at the same temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and it was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol = 98:2~80:20) to obtain the title compound (14 mg) as a light brown solid. MS(ESI)m / z:170.1[M-OH] + , 1 H NMR(400MHz,DMSO-d6)δ ppm 4.74-4.83(3H,m),5.22(2H,s),6.42(1H,d,J=7.7Hz),6.91(1H,d,J=7.7Hz),8.12(1H,s),11.75(1H,brs)

[0743] (33-6)methyl [(6S)-4-(4'-{[(4-{[3-cyano-4-(hydroxymethyl)-1H-indole-7-yl]sulfamoyl}phenyl)methyl]carbamoyl}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 33)

[0744] [ka]

[0745] To a solution of Example Compound 33-5 (13 mg) and Reference Example Compound 10 (73 mg) in tetrahydrofuran (1.0 mL), pyridine (0.17 mL) was added at room temperature and the mixture was stirred at the same temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and methanol, washed once with saturated brine and water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (chloroform:methanol = 98:2~90:10) to obtain the title compound (29 mg) as a beige powder. MS(ESI)m / z:839.5[M+H] +

[0746] Example 34 (34-1)[(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetic acid (Example compound 34)

[0747] [ka]

[0748] To a mixed solution of Compound 1 (295 mg) in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), 0.72 mL of 2N lithium hydroxide aqueous solution was added and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added and the mixture was stirred, then concentrated under reduced pressure. The residue was suspended and washed with water, filtered, and dried to obtain the title compound (258 mg) as a yellow powder. MS(ESI)m / z:809.4[M+H] +

[0749] Example 35 (35-1) t-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl)-1-benzofuran-2-carboxylate (Example compound 35-1)

[0750] [ka]

[0751] A mixture of t-butyl 5-bromo-1-benzofuran-2-carboxylate (1.50 g), bis(pinacolate)diborone (1.41 g), 1,1'-(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (206 mg), and potassium acetate (991 mg) was mixed with 1,4-dioxane (17 mL), purged with nitrogen, and heated and stirred at 130°C for 30 minutes under microwave irradiation. Water, ethyl acetate, and activated carbon were added to the reaction mixture, and insoluble matter was filtered off with diatomaceous earth. The filtrate was then washed with ethyl acetate. The filtrate was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 90:10) to obtain the title compound (1.38 g) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 1.37(12H,s),1.63(9H,s),7.40(1H,d,J=1.0Hz),7.56(1H,d,J=8.7Hz),7.87(1H,dd,J=1.3,8.5Hz),8.15(1H,s)

[0752] (35-2) t-butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}-1-benzofuran-2-carboxylate (Example compound 35-2)

[0753] [ka]

[0754] A mixture of Reference Compound 1 (80 mg), Example Compound 35-1 (73 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 9 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (15 mg), potassium phosphate (123 mg), water (0.013 mL), and tetrahydrofuran (1.0 mL) was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (115 mg) as a white powder. MS(ESI) m / z: 597.5[M+H] +

[0755] (35-3) Methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1-benzofuran-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 35)

[0756] [ka]

[0757] To a solution of Example Compound 35-2 (111 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, toluene was added and the solvent was removed by distillation. The resulting residue was dissolved in N,N-dimethylformamide (2.0 mL), and Reference Example Compound 5 (64 mg), N,N-diisopropylethylamine (0.32 mL), and HATU (85 mg) were added at room temperature and the mixture was stirred at the same temperature for 1 hour. After diluting the reaction mixture with ethyl acetate, it was added to saturated sodium bicarbonate water, and the resulting precipitate (A) was filtered off. The filtrate was separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layer (B) was washed twice with saturated saline solution-water (1:1) and once with saturated saline solution. The filtrate (A) was dissolved in chloroform and combined with the organic layer (B), and after drying and filtering over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (104 mg) as a white powder. MS(ESI)m / z:863.5[M+H] +

[0758] Example 36 (36-1) Methyl [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]carbamate (Example compound 36-1)

[0759] [ka]

[0760] To a solution of 6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (200 mg) described in Japanese Patent Publication (JP-A-7-17941, Raw Material Preparation Example 1) in dichloromethane (6.0 mL), methyl chloroformate (0.048 mL) and N,N-diisopropylethylamine (0.15 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hours. Water was added to the reaction mixture, and after extraction twice with chloroform, the mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~97:3) to obtain the title compound (233 mg) as a pale orange powder. MS(ESI)m / z:416.3[M+H] +

[0761] (36-2) t-butyl 4'-{6-[(methoxycarbonyl)amino]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl}[1,1'-biphenyl]-4-carboxylate (Example compound 36-2)

[0762] [ka]

[0763] A mixture of Example Compound 36-1 (30 mg), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (25 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 4 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (6 mg), potassium phosphate (46 mg), water (0.005 mL), and tetrahydrofuran (0.36 mL) was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed once with water and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (39 mg) as a white powder. MS(ESI)m / z:558.4[M+H] +

[0764] (36-3) Methyl (4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)carbamate (Example compound 36)

[0765] [ka]

[0766] To a solution of Example Compound 36-2 (37 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, toluene was added and the solvent was removed by distillation. The resulting residue was dissolved in N,N-dimethylformamide (0.67 mL), and Reference Example Compound 5 (25 mg), N,N-diisopropylethylamine (0.12 mL), and HATU (31 mg) were added at room temperature and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was diluted with ethyl acetate and washed once with saturated sodium bicarbonate solution, twice with saturated saline solution-water (1:1), and once with saturated saline solution. After drying and filtering over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (43 mg) as a white powder. MS(ESI)m / z:824.5[M+H] +

[0767] Example 37 (37-1)N-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-4'-[(6S)-6-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxamide (Example Compound 37)

[0768] [ka]

[0769] Compound 34 (100 mg), 2-aminoethanol (12 mg), N,N-diisopropylethylamine (0.064 mL), and HATU (56 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture and stirred, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 80:20) to obtain the title compound (97 mg) as a white solid. MS(ESI) m / z: 852.5[M+H] +

[0770] Example 38 (38-1)N-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-4'-{(6S)-6-[2-(dimethylamino)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl}[1,1'-biphenyl]-4-carboxamide (Example compound 38)

[0771] [ka]

[0772] In Example 37, the title compound was obtained as a milky white solid by using dimethylamine hydrochloride instead of 2-aminoethanol and carrying out the same reaction and treatment as in (37-1). MS(ESI)m / z:836.5[M+H] +

[0773] Example 39 (39-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenoxy}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 39)

[0774] [ka]

[0775] In Example 25, 2-(4-bromophenoxy)ethaneamine was used instead of 4-bromo-3-fluorophenylmethaneamine hydrochloride, and the same reaction and treatment as in (25-1)-(25-2) was carried out to obtain the title compound as a beige powder. MS(ESI)m / z:853.5[M+H] +

[0776] Example 40 (40-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-3'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 40)

[0777] [ka]

[0778] To a solution of Reference Compound 12 (63 mg) and Reference Compound 11 (53 mg) in N,N-dimethylformamide (1.3 mL), N,N-diisopropylethylamine (0.063 mL) and HATU (56 mg) were added at room temperature and the mixture was stirred for 1.5 hours at the same temperature. Water was added to the reaction mixture, the precipitate was filtered off and washed with water. The filtrate was dissolved in chloroform, dried by filtration over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (61 mg) as a pale yellow powder. MS(ESI)m / z:855.5[M+H] +

[0779] Example 41 (41-1) Methyl [(6S)-4-{3'-chloro-4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 41)

[0780] [ka]

[0781] In Example 40, the title compound (115 mg) was obtained as a white powder by using Reference Compound 13 (80 mg) instead of Reference Compound 12 and performing the same reaction and treatment. MS(ESI)m / z:871.5[M+H] +

[0782] Example 42 (42-1) Methyl [(6S)-4-{4'-[({4-[(4-bromo-3-cyano-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 42)

[0783] [ka]

[0784] In Example 7, Reference Example Compound 15 (24 mg) was used instead of Example Compound 7-2, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (56 mg) as a pale yellow solid. MS(ESI)m / z:887.3,889.3[M+H] +

[0785] Example 43 (43-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-ethyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 43)

[0786] [ka]

[0787] A mixture of Reference Compound 16 (14 mg), pyridine (0.059 mL), tetrahydrofuran (2.0 mL), and Reference Compound 10 (50 mg) was stirred at room temperature for 24 hours. The reaction solution was diluted and dissolved with a mixture of tetrahydrofuran and ethyl acetate (1:1) and a small amount of methanol. The organic layer was treated once with a mixture of saturated saline and 1N hydrochloric acid solution, and once with saturated saline. The mixture was washed once with saturated sodium bicarbonate solution and once with saturated saline solution, then dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution - acetonitrile) to obtain the title compound (42 mg) as a pale yellow solid. MS(ESI)m / z:837.5[M+H] +

[0788] Example 44 (44-1) 7-amino-4-cyclopropyl-1H-indole-3-carbonitride (Example compound 44-1)

[0789] [ka]

[0790] In a 1.9 mL solution of mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) in tetrahydrofuran, 4.6 mL of 0.5 M cyclopropylzinc bromide / tetrahydrofuran solution was added under a nitrogen atmosphere and ice cooling, and the mixture was stirred at room temperature for 50 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were then added and the mixture was separated. The organic layer was washed once with saturated sodium bicarbonate solution and once with saturated brine, then dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50~20:80), followed by preparative HPLC (10 mM ammonium carbonate aqueous solution - acetonitrile) to obtain the title compound (26 mg) as a white solid. MS(ESI) m / z: 198.1[M+H] +

[0791] (44-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-cyclopropyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 44)

[0792] [ka]

[0793] In Example 7, instead of Example Compound 7-2, Example Compound 44-1 (18 mg) was used, and the same reaction and treatment as in (7-3) was carried out to obtain the title compound (47 mg) as a pale yellow solid. MS(ESI)m / z:849.5[M+H] +

[0794] Example 45 (45-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 45)

[0795] [ka]

[0796] To a solution of Reference Example Compound 18-1 (85 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, toluene was added and the solvent was removed by distillation. The resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Example Compound 5 (56 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, the precipitate was filtered off and washed with water. The filtrate was dissolved in chloroform, dried by filtration over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (87 mg) as a white powder. MS(ESI)m / z:841.5[M+H] +

[0797] Example 46 (46-1) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl]-2'-fluoro[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 46)

[0798] [ka]

[0799] To a solution of Reference Compound 18-1 (85 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, toluene was added and the solvent was removed by distillation. The resulting residue was dissolved in N,N-dimethylformamide (1.5 mL), and Reference Compound 11 (64 mg), N,N-diisopropylethylamine (0.26 mL), and HATU (68 mg) were added at room temperature and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, the precipitate was filtered off and washed with water. The filtrate was dissolved in chloroform, dried by filtration over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (65 mg) as a white powder. MS(ESI)m / z:855.5[M+H] +

[0800] Example 47 (47-1) t-butyl 2-chloro-4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Example compound 47-1)

[0801] [ka]

[0802] In Reference Example 18, the title compound (374 mg) was obtained as a crude white powder by performing the same reaction and treatment using Reference Example Compound 3 (300 mg) and 4-bromo-3-chlorobenzoate t-butyl (207 mg) instead of 4-bromo-3-fluorobenzoate t-butyl. MS(ESI)m / z: 591.4,593.4[M+H] +

[0803] (47-2) Methyl [(6S)-4-{2'-chloro-4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 47)

[0804] [ka]

[0805] In Example 45, the title compound (221 mg) was obtained as a beige powder by using Example Compound 47-1 (180 mg) instead of Reference Example Compound 18-1 and performing the same reaction and treatment. MS(ESI)m / z:857.5,859.5[M+H] +

[0806] Example 48 (48-1) Methyl [(6S)-4-{2'-chloro-4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 48)

[0807] [ka]

[0808] In Example 46, the title compound (189 mg) was obtained as a beige powder by using Example Compound 47-1 (180 mg) instead of Reference Example Compound 18-1 and performing the same reaction and treatment. MS(ESI)m / z:871.5,873.5[M+H] +

[0809] Example 49 (49-1) Methyl [(6S)-4-(4-{2-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-1,3-benzoxazole-5-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 49)

[0810] [ka]

[0811] Reference compound 3 (200 mg), methyl 5-bromo-benzoxazole-2-carboxylate (121 mg), palladium acetate (9 mg), S-phos (32 mg), potassium fluoride (69 mg), and water (0.026 mL) were stirred in tetrahydrofuran (5.0 mL) under a nitrogen atmosphere and microwave irradiation at 100°C for 1 hour. The mixture was filtered with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain an orange viscous substance. The obtained viscous substance, along with reference compound 5 (134 mg), 1H-1,2,4-triazole (6 mg), and triethylamine (0.055 mL), were heated under reflux in tetrahydrofuran (5.0 mL) for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 95:5) to obtain the title compound (190 mg) as a milky white solid. MS(ESI)m / z:864.4[M+H] +

[0812] Example 50 (50-1) t-butyl 4'-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]-3-methyl[1,1'-biphenyl]-4-carboxylate (Example compound 50-1)

[0813] [ka]

[0814] Reference compound 3 (100 mg) was dissolved in tetrahydrofuran (2.0 mL), and t-butyl 4-bromo-2-methylbenzoate (65 mg), tetrakis(triphenylphosphine)palladium (0) (23 mg), potassium phosphate (126 mg), and water (0.013 mL) were added. The mixture was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50~0:100) to obtain the title compound (117 mg) as a crude white powder. MS(ESI) m / z: 571.3 [M+H] +

[0815] (50-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methyl[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 50)

[0816] [ka]

[0817] To a solution of Example Compound 50-1 (113 mg) in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, toluene was added and the solvent was removed by distillation. The resulting residue was dissolved in N,N-dimethylformamide (2.0 mL), and Reference Example Compound 5 (74 mg), N,N-diisopropylethylamine (0.34 mL), and HATU (90 mg) were added at room temperature and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, the precipitate was filtered off and washed with water. The filtrate was dissolved in chloroform, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (121 mg) as a white powder. MS(ESI)m / z:837.5[M+H] +

[0818] Example 51 (51-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-(trifluoromethyl)[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 51)

[0819] [ka]

[0820] In Example 50, 4-bromo-2-trifluoromethylbenzoate t-butyl was used instead of 4-bromo-2-methylbenzoate t-butyl, and the same reaction and treatment as in (50-1)-(50-2) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:891.5[M+H] +

[0821] Example 52 (52-1) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]-3'-methoxy[1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example Compound 52)

[0822] [ka]

[0823] In Example 50, 4-bromo-2-methoxybenzoate t-butyl was used instead of 4-bromo-2-methylbenzoate t-butyl, and the same reaction and treatment as in (50-1)-(50-2) was carried out to obtain the title compound as a white powder. MS(ESI)m / z:853.5[M+H] +

[0824] Example 53 (53-1) t-butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}pyridine-2-carboxylate (Example compound 53-1)

[0825] [ka]

[0826] Compound 3 (100 mg), t-butyl 5-bromopyridine-2-carboxylate (77 mg), tetrakis(triphenylphosphine)palladium (0) (23 mg), potassium phosphate (126 mg), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100°C for 0.5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (109 mg) as a colorless viscous substance. MS(ESI)m / z: 558.5[M+H] +

[0827] (53-2) Methyl [(6S)-4-(4-{6-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-3-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 53)

[0828] [ka]

[0829] To a solution of Example Compound 53-1 (109 mg) in chloroform (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotropic distillation was performed twice with toluene. The residue and Reference Example Compound 5 (73 mg), N,N-diisopropylethylamine (0.17 mL), and HATU (89 mg) were stirred in N,N-dimethylformamide (3.0 mL) at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was stirred, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (104 mg) as a milky white solid. MS(ESI)m / z:824.7[M+H] +

[0830] Example 54 (54-1) Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]pyridine-2-yl}phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 54)

[0831] [ka]

[0832] In Example 53, the title compound was obtained as a milky white solid by using t-butyl 6-bromopyridine-3-carboxylate instead of t-butyl 5-bromopyridine-2-carboxylate and carrying out the same reaction and treatment as in (53-1)-(53-2). MS(ESI)m / z:824.7[M+H] +

[0833] Example 55 (55-1) t-butyl 4'-[(6S)-2-(hydroxymethyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl][1,1'-biphenyl]-4-carboxylate (Example compound 55-1)

[0834] [ka]

[0835] A mixture of methyl [(6S)-4-(4-chlorophenyl)-2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (500 mg), (4-t-butoxycarbonylphenyl)boronic acid (386 mg), potassium phosphate (616 mg), tetrahydrofuran (5.0 mL), water (0.52 mL), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl aminobiphenyl palladium chloride pre-catalyst (42 mg), and S-phos (24 mg), as described in WO2006 / 129623, was stirred under heating reflux for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol = 99:1~90:10) to obtain the title compound (610 mg) as a milky white solid. MS(ESI)m / z:573.2[M+H] +

[0836] (55-2) Methyl [(6S)-4-{4'-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl][1,1'-biphenyl]-4-yl}2-(hydroxymethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 55)

[0837] [ka]

[0838] To a solution of Example Compound 55-1 (80 mg) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue and Reference Example Compound 5 (57 mg) were dissolved in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.073 mL) was added at room temperature, and HATU (69 mg) was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with a mixture of ethyl acetate and tetrahydrofuran (1:1), and 1N hydrochloric acid and saturated saline solution were added, and the mixture was separated. The organic layer was washed once with saturated saline solution, once with saturated sodium bicarbonate solution, and once with saturated saline solution. After drying and filtration with anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0~85:15) to obtain the title compound (51 mg) as a pale yellow solid. MS(ESI)m / z:839.4[M+H] +

[0839] Example 56 (56-1) Methyl {(6S)-2,3,9-trimethyl-4-[4-(1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example compound 56-1)

[0840] [ka]

[0841] A mixture of Reference Example Compound 1 (200 mg), t-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (208 mg), X-Phos aminobiphenylpalladium chloride pre-catalyst (38 mg), X-Phos (23 mg), potassium phosphate (307 mg), water (0.031 mL), and tetrahydrofuran (2.4 mL) was stirred at 90°C for 0.5 hours under microwave irradiation. Ethyl acetate and saturated brine were added to the reaction mixture, insoluble matter was filtered off, and the filtrate was separated. The organic layer was washed once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in chloroform (1.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. The solvent was removed under reduced pressure, followed by azeotropic concentration with toluene. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol = 100:0~96:4) to obtain the title compound (244 mg) as a pale yellow powder. MS(ESI)m / z:512.3[M+H] +

[0842] (56-2) Methyl [(6S)-4-{4-[2-({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]phenyl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 56)

[0843] [ka]

[0844] A mixture of Example Compound 56-1 (60 mg), Reference Example Compound 5-1 (44 mg), and chloroform (2.0 mL) was mixed with sodium triacetoxyborohydride (50 mg) at room temperature and stirred at the same temperature for 22 hours. Another 50 mg of sodium triacetoxyborohydride was added at room temperature and stirred at the same temperature for 8 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and stirred at room temperature for 30 minutes. Saturated saline solution was added, and the mixture was extracted three times with chloroform. The extract was dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (10 mM ammonium carbonate aqueous solution - acetonitrile) to obtain the title compound (74 mg) as a pale yellow solid. MS(ESI) m / z: 835.5[M+H] +

[0845] Example 57 (57-1) N-(3-cyano-4-methyl-1H-indole-7-yl)-4-fluorobenzene-1-sulfonamide (Example compound 57-1)

[0846] [ka]

[0847] A mixture of Reference Compound 9 (300 mg), pyridine (0.71 mL), and tetrahydrofuran (3.0 mL) was mixed with 4-fluorobenzenesulfonyl chloride (375 mg) at room temperature and stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, saturated brine and 1N hydrochloric acid were added, and the mixture was separated. The organic layer was washed twice with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (580 mg) as a brown solid. MS(ESI)m / z: 328.1[MH] -

[0848] (57-2) 4-[(2-aminoethyl)amino]-N-(3-cyano-4-methyl-1H-indole-7-yl)benzene-1-sulfonamide (Example compound 57-2)

[0849] [ka]

[0850] A mixture of Example Compound 57-1 (200 mg), ethylenediamine (0.61 mL), and tetrahydrofuran (1.0 mL) was heated and stirred at 150°C for 0.5 hours under microwave irradiation. Saturated saline solution was added to the reaction mixture, and the mixture was extracted three times with a 1:1 mixture of ethyl acetate and tetrahydrofuran. The extracts were combined, washed once with a small amount of saturated saline solution, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was suspended and washed with ethyl acetate, and then filtered to obtain the title compound (180 mg) as a brown powder. MS(ESI)m / z:370.2[M+H] +

[0851] (57-3) Methyl [(6S)-4-{4'-[(2-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]anilino}ethyl)carbamoyl][1,1'-biphenyl]-4-yl}-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 57)

[0852] [ka]

[0853] A mixture of Example Compound 57-2 (41 mg), Reference Example Compound 4 (50 mg), N,N-diisopropylethylamine (0.043 mL), and N,N-dimethylformamide (1.0 mL) was mixed with HATU (49 mg) under ice cooling and stirred at the same temperature for 5 minutes and at room temperature for 3 hours. The reaction mixture was diluted with a 1:1 mixture of ethyl acetate and tetrahydrofuran, washed once with saturated sodium bicarbonate solution and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was suspended and washed with acetonitrile-water, filtered, and washed with water to obtain the title compound (45 mg) as a pink powder. MS(ESI)m / z:852.5[M+H] +

[0854] Example 58 (58-1) 3-[4-(benzylsulfanyl)phenyl]propan-1-ol (Example compound 58-1)

[0855] [ka]

[0856] A mixture of 3-(4-bromophenyl)propan-1-ol (1000 mg), benzyl mercaptan (0.55 mL), N,N-diisopropylethylamine (2.41 mL), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (Xantphos, 269 mg), tris(dibenzylideneacetone)dipalladium (213 mg), and toluene (15.0 mL) was stirred at 100°C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was purified directly by silica gel column chromatography (hexane:ethyl acetate = 60:40~20:80, pre-column: NH silica gel) to obtain the title compound (681 mg) as a red solid. 1 1H NMR (400MHz, CDCl3)δ ppm 1.23(1H,t,J=5.3Hz),1.81-1.91(2H,m),2.62-2.71(2H,m),3.61-3.70(2H,m),4.08(2H,s),7.05-7.11(2H,m),7.19-7.31(7H,m)

[0857] (58-2) 2-(4-{3-[4-(benzylsulfanyl)phenyl]propoxy}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example Compound 58-2)

[0858] [ka]

[0859] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and Example Compound 58-1 (281 mg) were dissolved in toluene (3.0 mL). Cyanomethylenetrimethylphosphoran (157 mg) was added at room temperature, and the mixture was stirred at 150°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. The reaction mixture was diluted with ethyl acetate, washed once with saturated brine-water (1:1), and once with saturated brine. After drying and filtering over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5) to obtain the title compound (338 mg) as a colorless viscous substance. 1 H NMR(400MHz,CDCl3)δ ppm 1.33(12H,s),2.00-2.12(2H,m),2.76(2H,t,J=7.6Hz),3.96(2H,t,J=6.2Hz),4.08(2H,s),6.87(2H ,d,J=8.7Hz),7.09(2H,d,J=8.3Hz),7.22(3H,d,J=8.3Hz),7.25-7.28(4H,m),7.74(2H,d,J=8.7Hz)

[0860] (58-3) Methyl [(6S)-4-(4'-{3-[4-(benzylsulfanyl)phenyl]propoxy}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 58-3)

[0861] [ka]

[0862] A mixture of Reference Compound 1 (100 mg), Example Compound 58-2 (122 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos, 12 mg), X-Phos aminobiphenylpalladium(II) methanesulfonate pre-catalyst (21 mg), potassium phosphate (154 mg), water (0.016 mL), and tetrahydrofuran (1.2 mL) was stirred at 90°C for 0.5 hours under a nitrogen atmosphere and microwave irradiation. Example Compound 58-2 (67 mg), X-Phos (12 mg), and X-Phos aminobiphenylpalladium(II) methanesulfonate pre-catalyst (21 mg) were added, and the mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere and microwave irradiation. The reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to obtain the title compound (147 mg) as a pale yellow powder. MS(ESI) m / z: 713.5[M+H] +

[0863] (58-4) Methyl [(6S)-4-(4'-{3-[4-(chlorosulfonyl)phenyl]propoxy}[1,1'-biphenyl]-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetate (Example compound 58-4)

[0864] [ka]

[0865] To a solution of compound 58-3 (141 mg) in acetonitrile (3.0 mL) and 2N hydrochloric acid (0.60 mL), N-chlorosuccinimide (93 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. N-chlorosuccinimide (6 mg) was added, and the mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated brine-water (1:1), and saturated brine, and then dried and filtered over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 98:2) to obtain the title compound (134 mg) as a pale yellow powder. MS(ESI)m / z:671.4[M-Cl+H2O] +

[0866] (58-5) Methyl {(6S)-4-[4'-(3-{4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}propoxy)[1,1'-biphenyl]-4-yl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl}acetate (Example Compound 58)

[0867] [ka]

[0868] To a solution of Example Compound 58-4 (130 mg) and Reference Example Compound 9 (39 mg) in tetrahydrofuran (2.6 mL), pyridine (0.15 mL) was added at room temperature and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, washed once with 1N hydrochloric acid and once with saturated brine, dried and filtered over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform:methanol = 95:5~50:50), and then purified again by silica gel column chromatography (chloroform:methanol = 98:2~95:5) to obtain the title compound (52 mg) as a light brown powder. MS(ESI)m / z:824.5[M+H] +

[0869] Example 59 (59-1) t-butyl 5-{4-[(6S)-6-(2-methoxy-2-oxoethyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-4-yl]phenyl}thiophene-2-carboxylate (Example compound 59-1)

[0870] [ka]

[0871] Compound 3 (100 mg), t-butyl 5-bromothiophene-2-carboxylate (78 mg), tetrakis(triphenylphosphine)palladium (0) (23 mg), potassium phosphate (126 mg), and water (0.014 mL) were stirred in tetrahydrofuran (4.0 mL) under a nitrogen atmosphere and microwave irradiation at 100°C for 0.5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0~95:5) to obtain the title compound (89 mg) as a pale yellow solid. MS(ESI) m / z: 563.2 [M+H] +

[0872] (59-2) Methyl [(6S)-4-(4-{5-[({4-[(3-cyano-4-methyl-1H-indole-7-yl)sulfamoyl]phenyl}methyl)carbamoyl]thiop...

Claims

1. Formula (20-1): 【Chemistry 1】 In the presence of a condensing agent and a base, the compound represented by formula (20-2): 【Chemistry 2】 By reacting with a compound represented by formula (I) or its hydrochloride salt, the compound (I) is produced. 【Transformation 3】 Use for producing a compound represented by or a pharmaceutically acceptable salt thereof, In the above formula, A represents a ring selected from 5-6 member aromatic heterocycles and cycloalkane rings containing 1-3 atoms selected from aromatic hydrocarbon rings, oxygen, sulfur, and nitrogen. The ring is, halogen atom; Hydroxyl group; Cyano group; Hydroxycarbonyl group; Oxo group; Thioxo group; Alkyl groups that may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups; An alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; Alkoxycarbonyl groups which may be substituted with a group selected from halogen atoms, hydroxyl groups, alkoxy groups, and cyano groups; ----N(R ７ａ )(R ７ｂ ); -N(R) ７ａ ) (Caution ７ｂ );and -N(R ７ｃ )----R ７ｄ ; It may also be substituted with a group selected from the following: Substructure: 【Chemistry 4】 However, the following formula: 【Transformation 5】 [In the formula, R ａ This represents a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; R ａ’ represents a hydrogen atom; a halogen atom; a hydroxy group; a cyano group; an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; an alkoxycarbonyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group and a cyano group; or -CO-N(R ７ａ )(R ７ｂ ), and R ａ’’ is a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; an alkoxycarbonyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; or -CO-N(R ７ａ ) (Caution ７ｂ ) indicates. As shown, R Ｚ３ This represents a group selected from: hydrogen atom; halogen atom; hydroxyl group; cyano group; hydroxycarbonyl group; alkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; cycloalkyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxy group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with a group selected from halogen atom, hydroxyl group, alkoxy group and cyano group. R Ｚ４ and R Ｚ５ These independently represent a group selected from: a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkoxy group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. Substructure: 【Transformation 6】 This is expressed by the following formula (Ea) or (Ec): 【Transformation 7】 Show, Substructure: 【Transformation 8】 teeth, 【Chemistry 9】 Show, L represents a group selected from: a divalent aromatic hydrocarbon group; a divalent aliphatic heterocyclic group; a divalent aromatic heterocyclic group which may be partially hydrogenated; an alkylene group; a cycloalkylene group; an alkenylene group; and an alkylene group. The group may be substituted with substituents selected from halogen atoms; hydroxyl groups; cyano groups; hydroxycarbonyl groups; alkyl groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and alkoxy groups which may be substituted with groups selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups. T is -CO-NR ７ｃ - indicates, Does M represent a single bond? -O-;-S-;-NR ７ａ -;-CO-;-SO-;-SO ２ -;-CO-NR ７ｃ -;-NR ７ｃ -CO-; -SO ２ -NR ７ｃ -;-NR ７ｃ -SO ２ -;-NR ７ａ -CO-NR ７ｂ -;- (OCH ２ CH ２ ) ｍ -;-OR-R ７ｒ -;-R ７ｒ -O-;-S-R ７ｒ -;-R ７ｒ -S-;-NR ７ａ -R ７ｒ -;-R ７ｒ -NR ７ａ -;-CO-NR ７ｃ -R ７ｒ -;-R ７ｒ -CO-NR ７ｃ -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; an alkylylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; and a group which may be substituted with substituents selected from a) halogen atoms, b) hydroxyl groups, c) cyano groups, d) oxo groups, e) alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups, and f) a divalent aliphatic heterocyclic group which may be substituted with substituents selected from alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups, alkoxy groups and cyano groups; -L-T-M- is, in whole or in part, -O-O-, -S-S-, -NR ７ａ -NR ７ａ -, -O-S-, -S-O-, -O-NR ７ａ -, -NR ７ａ -O-, -S-NR ７ａ - and -NR ７ａ It does not indicate the group selected from -S-, Further substructure: 【Chemistry 10】 teeth, 【Chemistry 11】 Show, n represents 2, m represents an integer from 1 to 6. R ５ This represents a hydrogen atom. R ６ａ and R ６ｂ These independently represent a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, and a cyano group. R ７ａ and R ７ｂ These independently represent a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group. R bonded to the same nitrogen atom ７ａ and R ７ｂ It may bond to form an aliphatic heterocycle containing one nitrogen atom, which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group, along with the nitrogen atom. R ７ｃ This represents a hydrogen atom. R ７ｄ This represents a hydrogen atom; or an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. R ７ｒ This indicates a group selected from: an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; an alkenylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group; or an alkylene group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, and a cyano group. R ８ａ and R ８ｂ These independently represent groups selected from hydrogen atoms; halogen atoms; hydroxyl groups; and cyano groups. R ９ａ and R ９ｂ These represent groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, and a cyano group. R １０ａ and R １０ｂ These are, independently of each other, hydrogen atoms; -N(R ７ｃ )-CO-OR ７ｄ The substituents selected from ; and alkyl groups are shown, The alkyl group is, Halogen atom; hydroxyl group; cyano group; alkoxy group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; alkoxycarbonyl group which may be substituted with substituents selected from halogen atom, hydroxyl group, alkoxy group and cyano group; hydroxycarbonyl group; and -CO-N(R ７ａ ) (Caution ７ｂ ); may be substituted with substituents selected from: R １１ is a hydrogen atom; and an alkyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group and a cyano group; use.

2. In the above formula, A is a ring selected from a benzene ring; a pyridine ring; and a cycloalkane ring. R ａ However, it is an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R ａ’ However, it is an alkyl group which may be substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R ａ’’ However, it is a hydrogen atom; a halogen atom; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or a cyano group. R Ｚ３ However, it is a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; a cycloalkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; or an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; R Ｚ４ and R Ｚ５ Each is independently of the others a hydrogen atom; or an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group; Substructure: 【Chemistry 12】 However, the following formula (Ea): 【Chemistry 13】 And, L is a group selected from: an alkylylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aromatic hydrocarbon group which may be substituted with substituents selected from a) halogen atoms, b) hydroxyl groups, c) cyano groups, d) alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups, and e) alkoxy groups which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; a divalent aliphatic heterocyclic group containing one nitrogen atom which may be substituted with substituents selected from halogen atoms, hydroxyl groups and cyano groups; and a divalent aromatic heterocyclic group containing one to two atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may be partially hydrogenated. The aromatic heterocyclic group may be substituted with substituents selected from halogen atoms, hydroxyl groups, cyano groups, and oxo groups. T is -CO-NR ７ｃ - indicates, Is M a single bond? -R ７ｒ -O-;-R ７ｒ -NR ７ａ -; an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; an alkynylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups; and a divalent aliphatic heterocyclic group; a group selected from these, R ６ａ and R ６ｂ These are groups that are independently selected from a hydrogen atom; a halogen atom; a cyano group; and an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxyl group, and a cyano group. R ７ａ and R ７ｂ However, each alkyl group may be independently substituted with a hydrogen atom; or a substituent selected from halogen atoms, hydroxyl groups, and cyano groups. R ７ｃ That is a hydrogen atom, R ７ｄ This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R ７ｒ This is an alkylene group which may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. R ８ａ and R ８ｂ All of them are hydrogen atoms, R ９ａ and R ９ｂ is an alkyl group which may be independently substituted by a substituent selected from a halogen atom, a hydroxy group and a cyano group. R １０ａ hydrogen atoms; as well as halogen atoms, hydroxyl groups, cyano groups, -NH-CO-OR ７ｄ , -CO-N(R ７ａ ) (Caution ７ｂ A group selected from: an alkyl group which may be substituted with a substituent selected from an alkoxycarbonyl group and a hydroxycarbonyl group; R １０ｂ That is a hydrogen atom, R １１ This alkyl group may be substituted with substituents selected from halogen atoms, hydroxyl groups, and cyano groups. Use as described in claim 1.

3. In the above formula, R ａ is a hydrogen atom; or an alkyl group, R ａ’ However, it is a hydrogen atom; or an alkyl group, R ａ’’ However, it is a hydrogen atom; a halogen atom; an alkyl group; or a cyano group. R Ｚ３ However, it is a hydrogen atom; a halogen atom; a cyano group; an alkyl group which may be substituted with one to three substituents selected from a halogen atom and a hydroxyl group; a cycloalkyl group; or an alkoxy group. R Ｚ４ and R Ｚ５ Each is independently a hydrogen atom; or an alkyl group; Substructure: 【Chemistry 14】 However, the following formula (Ea): 【Chemistry 15】 And, L is a group selected from: an alkylylene group; a divalent aromatic hydrocarbon group which may be substituted with one or two substituents selected from a halogen atom, a hydroxyl group, an alkyl group which may be substituted with one to three halogen atoms, and an alkoxy group; a divalent aliphatic heterocyclic group which contains one nitrogen atom; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains one or two atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. When the aromatic heterocyclic group is a divalent aromatic heterocyclic group containing one or two atoms selected from nitrogen, oxygen, and sulfur atoms, which are partially hydrogenated, it may be substituted with an oxo group. T is -CO-NR ７ｃ - and Is M a single bond? -R ７ｒ -O-;-R ７ｒ -NR ７ａ -; an alkylene group which may be substituted with one hydroxyl group; an alkylylene group; and a divalent aliphatic heterocyclic group; are selected from these groups. R ６ａ and R ６ｂ These groups are independently selected from hydrogen atoms; halogen atoms; cyano groups; and alkyl groups. R ７ａ and R ７ｂ However, they are hydrogen atoms or alkyl groups, independently of each other. R ７ｃ That is a hydrogen atom, R ７ｄ is an alkyl group, R ７ｒ This is an alkylene group, R ８ａ and R ８ｂ All of them are hydrogen atoms, R ９ａ and R ９ｂ However, these alkyl groups may be substituted with one hydroxyl group independently of each other. R １０ａ is a hydrogen atom; and -NH-CO-OR ７ｄ , -CO-N(R ７ａ ) (Caution ７ｂ A group selected from: an alkyl group which may be substituted with one substituent selected from a cyano group, an alkoxycarbonyl group and a hydroxycarbonyl group; R １０ｂ That is a hydrogen atom, R １１ is an alkyl group. The use described in claim 1.

4. In the above formula, A is a benzene ring, R ａ However, it is a hydrogen atom, R １０ａ However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. L is a group selected from a halogen atom, an alkyl group which may be substituted with 1 to 2 substituents selected from an alkoxy group, and a halogen atom; and a divalent aromatic heterocyclic group which may be partially hydrogenated and contains 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. M is an alkylene group which may be substituted with one substituent selected from a hydroxyl group and a cyano group. The use described in claim 1.

5. In the above formula, R ａ’ However, it is a hydrogen atom, R ａ’’ However, it is a cyano group, R Ｚ３ However, it is an alkyl group or alkoxy group which may be substituted with 1 to 3 halogen atoms or hydroxyl groups, R Ｚ４ That is a hydrogen atom, R Ｚ５ That is a hydrogen atom. The use described in claim 1.

6. In the above formula, R ８ａ and R ８ｂ All of them are hydrogen atoms, R ９ａ and R ９ｂ However, these alkyl groups may be substituted with one hydroxyl group independently of each other. R １０ａ However, it is an alkyl group that may be substituted with one alkoxycarbonyl group. R １０ｂ That is a hydrogen atom, R １１ is an alkyl group. The use described in claim 1.

7. In the above formula, L is a phenylene group or a pyrazinediyl group, which may be substituted with one or two substituents selected from halogen atoms and alkyl groups. T is -CO-NR ７ｃ - and R ７ｃ That is a hydrogen atom, M is -CH ２ - or -CH(CH ３ ) - is The use described in claim 1.

8. The compound represented by formula (20-1) is formula (C-1): 【Chemistry 16】 [In the formula, P Ｃ [This symbol is a protecting group for carboxylic acids, and the other symbols have the same meaning as above.] Protecting group P of the compound represented by Ｃ Obtained by removing The use described in claim 1.

9. A compound represented by formula (20-1) or formula (C-1) is: 【Chemistry 17】 A compound represented by the formula: [Chemistry 18] A compound represented by the formula: 【Chemistry 19】 Compounds represented by the formula: 【Chemistry 20】 The use according to claim 1 or 8, selected from the group consisting of compounds represented by the following:

10. A compound represented by formula (20-2) or its hydrochloride salt is, formula: 【Chemistry 21】 A compound represented by the formula: 【Chemistry 22】 Compounds represented by the formula: 【Chemistry 23】 The use according to claim 1, selected from the group consisting of compounds represented by

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